5-fluoro-c-(aryl or heterocyclyl)-glycoside derivatives useful as dual sglt1 / sglt2 modulators

ABSTRACT

The present invention is directed to 5-fluoro-C-(aryl or heterocyclyl)-glycoside derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by SGLT activity, more particularly dual SGLT1/2 activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 62/547,911, filed Aug. 21, 2017, the disclosure of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to 5-fluoro-C-(aryl orheterocyclyl)-glycoside derivatives, pharmaceutical compositionscontaining them and their use in the treatment of disorders andconditions modulated by SGLT activity, more particularly dual SGLT1/2activity. More particularly, the compounds of the present invention areuseful in the treatment of for example, Type II diabetes mellitus,Syndrome X, and complications and symptoms associated with saiddisorders.

BACKGROUND OF THE INVENTION

Diabetes is a chronic disorder affecting carbohydrate, fat and proteinmetabolism in animals.

Type I diabetes mellitus, which comprises approximately 10% of alldiabetes cases, was previously referred to as insulin-dependent diabetesmellitus (IDDM) or juvenile onset diabetes. This disease ischaracterized by a progressive loss of insulin secretory function bybeta cells of the pancreas. This characteristic is also shared bynon-idiopathic, or “secondary”, diabetes having its origins inpancreatic disease. Type I diabetes mellitus is associated with thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction. Therapy forIDDM patients has consistently focused on administration of exogenousinsulin, which may be derived from various sources (e.g., human, bovine,porcine insulin). The use of heterologous species material gives rise toformation of anti-insulin antibodies which have activity limitingeffects and result in progressive requirements for larger doses in orderto achieve desired hypoglycemic effects.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus orNIDDM) is a metabolic disorder involving the dysregulation of glucosemetabolism and impaired insulin sensitivity. Type II diabetes mellitususually develops in adulthood and is associated with the body'sinability to utilize or make sufficient insulin. In addition to theinsulin resistance observed in the target tissues, patients sufferingfrom type II diabetes mellitus have a relative insulin deficiency—thatis, patients have lower than predicted insulin levels for a given plasmaglucose concentration. Type II diabetes mellitus is characterized by thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction. Typicaltreatment of Type II diabetes mellitus focuses on maintaining the bloodglucose level as near to normal as possible with lifestyle modificationrelating to diet and exercise, and when necessary, the treatment withantidiabetic agents, insulin or a combination thereof. NIDDM that cannotbe controlled by dietary management is treated with oral antidiabeticagents.

Syndrome X, also termed Insulin Resistance Syndrome (IRS), MetabolicSyndrome, or Metabolic Syndrome X, is recognized in some 2% ofdiagnostic coronary catheterizations. Often disabling, it presentssymptoms or risk factors for the development of Type II diabetesmellitus and cardiovascular disease, including impaired glucosetolerance (IGT), impaired fasting glucose (IFG), hyperinsulinemia,insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL),hypertension and obesity. Although insulin resistance is not alwaystreated in all Syndrome X patients, those who exhibit a prediabeticstate (e.g., IGT, IFG), where fasting glucose levels may be higher thannormal but not at the diabetes diagnostic criterion, is treated in somecountries (e.g., Germany) with metformin to prevent diabetes. Theanti-diabetic agents may be combined with pharmacological agents for thetreatment of the concomitant co-morbidities (e.g., antihypertensives forhypertension, hypolipidemic agents for lipidemia).

Hyperglycemia is one common characteristic of these diabetic disorders.Treatments of hyperglycemia are focused on excretion of excessiveglucose directly into urine, which involves sodium-glucosecotransporters (SGLTs), primarily found in the chorionic membrane of theintestine and kidney. In particular, renal reabsorption of glucose ismediated by SGLT1 and SGLT2 (MARSENIC, O., “Glucose Control by theKidney: An Emerging Target in Diabetes”, AM. J. Kidney Dis., 2009 May,pp 875-883, Vol. 53(5); WRIGHT, E. M., et al., “Biology of Human SodiumGlucose Transporters”, Physiol. Rev., 2011 April, pp 733-794, Vol.91(2)). SGLT1, a high-affinity low-capacity transporter with aNa⁺:glucose transport ratio of 2:1, is present in intestinal and renalepithelial cells (LEE, W. S., et al., “The High Affinity Na₊/GlucoseCotransporter. Re-evaluation of Function and Distribution ofExpression”, J. Biol. Chem., 1994 April 22, pp 12032-12039, Vol.269(16)). On the other hand, SGLT2, also known as SAAT1, a low-affinityhigh-capacity transporter with a Na⁺:glucose transport ratio of 1:1, isfound in the epithelium of the kidney (YOU, G., et al., “MolecularCharacteristic of Na(+)-coupled Glucose Transporters in Adult andEmbryonic Rat Kidney”, J. Biol. Chem., 1995 Dec. 8, pp 29365-29371, Vol.270(49); CHEN, J., et al., “Quantitative PCR Tissue Expression Profilingof the Human SGLT2 Gene and Related Family Members”, Diabetes Ther.,2010 December, pp 57-92, Vol. 1(2)). In addition, glucose absorption inthe intestine is primarily mediated by SGLT1 and SGLT2. Thus, inhibitionof SGLT1 and SGLT2 reduces plasma glucose through suppression of glucosereabsorption in the kidney, which was demonstrated in rodent models ofIDDM and NIDDM by increasing the excretion of glucose in urine andlowering blood glucose levels.

Non-alcoholic fatty liver disease (NAFLD) is one cause of a fatty liver,occurring when fat is deposited (steatosis) in the liver. NAFLD isconsidered to cover a spectrum of disease activity. This spectrum beginsas fatty accumulation in the liver (hepatic steatosis). A liver canremain fatty without disturbing liver function, but by varyingmechanisms and possible insults to the liver may also progress to becomeNASH, a state in which steatosis is combined with inflammation andfibrosis. Non-alcoholic steatohepatitis (NASH) is a progressive, severeform of NAFLD. Over a 10-year period, up to 20% of patients with NASHwill develop cirrhosis of the liver, and 10% will suffer death relatedto liver disease. The exact cause of NAFLD is still unknown, however,both obesity and insulin resistance are thought to play a strong role inthe disease process. The exact reasons and mechanisms by which thedisease progresses from one stage to the next are not known.

NAFLD has been linked to insulin resistance (IR) and the metabolicsyndrome (MS). As the renin-angiotensin system (RAS) plays a centralrole in insulin resistance, and subsequently in NAFLD and NASH, anattempt to block the deleterious effects of RAS overexpression has beenproposed a target for treatment. While many potential therapies testedin NASH target only the consequences of this condition, or try to “getrid” of excessive fat, angiotensin receptor blockers (ARBs) may act as atool for correction of the various imbalances that act in harmony inNASH/NAFLD. Indeed, by inhibiting RAS the intracellular insulinsignaling pathway may be improved, resulting in better control ofadipose tissue proliferation and adipokine production, as well as morebalanced local and systemic levels of various cytokines. At the sametime, by controlling the local RAS in the liver fibrosis may beprevented and the cycle that links steatosis to necroinflammation sloweddown. (GEORGESCU, E. F., in Advances in Therapy, 2008, pp 1141-1174,Vol. 25, Issue 11)

SCAFOGLIO, C., et al., in “Functional expression of sodium-glucosetransporters in cancer”, PNAS, 2015, pp E41111-E4119, Vol 112(3),describe the role of sodium-dependent glucose transporters (SGLTs) inpancreatic and prostate adenocarcinomas, and their role in cancer cellsurvival. SGLT2 was found to be functionally expressed in pancreatic andprostate adenocarcinomas and further found to block glucose uptake andreduce tumor growth and survival in a xenograft model of pancreaticcancer, suggesting that SGLT2 inhibitors could be useful in treatingcertain types of cancers.

There remains a need for SGLT inhibitor compounds that havepharmacokinetic and pharmacodynamic properties suitable for use as humanpharmaceuticals.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R¹ is selected from the group consisting of —C₁₋₄alkyl, hydroxysubstituted C₁₋₄alkyl, —CH₂—R¹⁰, C₃₋₆cycloalkyl, hydroxy substitutedC₃₋₆cycloalkyl, —C(O)OH and —C(O)O—(C₁₋₄alkyl);

wherein R¹⁰ is selected from the group consisting of fluoro, C₁₋₂alkoxy,cyano and NR^(A)R^(B); wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl;

R² is selected from the group consisting of hydrogen, halogen, hydroxy,C₁₋₄alkyl, —(C₁₋₄alkyl)-OH, C₁₋₄alkoxy, cyano substituted C₁₋₄alkoxy,C₂₋₄alkenyl, C₂₋₄alkenyl-oxy, benzyloxy and carboxy;

R³ is selected from the group consisting of hydrogen, halogen, C₁₋₄alkyland C₂₋₄alkenyl;

R⁴ is selected from the group consisting of hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy, fluorinatedC₁₋₂alkoxy, cyano substituted C₁₋₄alkoxy and C₃₋₆cycloalkyl;

alternatively, R² and R³ or R³ and R⁴ are taken together with the carbonatoms to which they are bound to form a ring structure selected from thegroup consisting of 2,3-dihydrofuranyl and 3,4-dihydro-2H-pyranyl;

wherein —R²—R³— is selected from the group consisting of —O—CH₂—CH₂—,—CH₂—CH₂—O—, —CH₂—O—CH₂—CH₂— and CH₂—CH₂—O—CH₂—; and wherein —R³—R⁴— isselected from the group consisting of —O—CH₂—CH₂—, —CH₂—CH₂—O—,—CH₂—O—CH₂—CH₂— and CH₂—CH₂—O—CH₂—;

wherein the 2,3-dihydrofuranyl or 3,4-dihydro-2H-pyranyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of hydroxy, methyl, ethyl, hydroxy-methyl- andhydroxyethyl-;

R⁵ and R⁶ are the same and are hydrogen;

is selected from the group consisting of C₅₋₁₂cycloalkyl,C₅₋₁₂cycloalkenyl, phenyl, heteroaryl and heterocyclyl;

wherein the phenyl, heteroaryl or heterocyclyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, hydroxy, oxo (i.e. ═O), C₁₋₄alkyl, C₁₋₄alkoxy,fluorinated C₁₋₂alkyl, fluorinated C₁₋₂alkoxy, cyano,2,5-dimethyl-thien-3-yl, 5-methyl-thiazol-2-yl and —C(O)—R¹¹;

wherein R¹¹ is selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, C₃₋₆cycloalkyl, azetidin-1-yl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl andthiazol-2-yl;

provided that when

is bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl (i.e. benzocyclobut-4-yl) orbicyclo[4.2.0]octan-3-yl, then R² and R³ or R³ and R⁴ are taken togetherwith the carbon atoms to which they are bound to form a ring structureselected from the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl;

wherein 2,3-dihydrofuranyl or 3,4-dihydro-2H-pyranyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of hydroxy, methyl, ethyl, hydroxy-methyl- andhydroxyethyl-;

provided further that when

is phenyl, wherein the phenyl is optionally substituted, then R² and R³or R³ and R⁴ are taken together with the carbon atoms to which they arebound to form a ring structure selected from the group consisting of2,3-dihydrofuranyl and 3,4-dihydro-2H-pyranyl;

provided further that when

is thienyl or pyridyl, then R² and R³ or R³ and R⁴ are taken togetherwith the carbon atoms to which they are bound to form a ring structureselected from the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl;

provided further that when R¹ is —CH₂OH, R² is H, R³ is H, R⁴ is H orCl, R⁵ is H and R⁶ is H, then

is other than benzothien-2-yl;

and isotopologues and pharmaceutically acceptable salts thereof.

The present invention is further directed to compounds of formula (V-S)

wherein A¹, A² and A³ are each an independently selected from the groupconsisting of C₁₋₈alkyl, C₃₋₆cycloalkyl, bicyclo[2.2.1]heptan-2-yl

phenyl and 3,5-di(trifluoromethyl)phenyl. The compounds of formula (V-S)are useful as intermediates in the synthesis of pharmaceutical agents.

The present invention is further directed to a process for thepreparation of the compound of formula (V-S)

wherein A¹, A² and A³ are each an independently selected from the groupconsisting of C₁₋₈alkyl, C₃₋₆cycloalkyl, bicyclo[2.2.1]heptan-2-yl,phenyl and 3,5-di(trifluoromethyl)phenyl;

comprising

reacting(2S,3R,4S,5R,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,with an acylating agent; in the presence of an inorganic or organicbase; neat, when in the presence of an organic base or when in thepresence of an inorganic base, in an organic solvent; at a temperaturein the range of from about −50° C. to about room temperature; to yieldthe corresponding compound of formula (A-1), wherein W is thecorresponding acyl group, preferably —C(O)-methyl, —C(O)-ethyl,—C(O)-benzyl, more preferably —C(O)-benzyl (benzoyl);

reacting the compound of formula (A-1) with a fluorinating agent; in anorganic solvent or mixture of organic solvents; at a temperature in therange of from about −50° C. to about room temperature; to yield thecorresponding compound of formula (A-2);

de-protecting the compound of formula (A-2) to yield(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol;

reacting(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolwith a trialkyl silyl reagent; in the presence of an organic base; in anorganic solvent or mixture of organic solvents; at a temperature in therange of from about 0° C. to about 50° C.; to yield the correspondingcompound of formula (A-3) wherein A¹, A² and A³ are the correspondingalkyl groups;

reacting the compound of formula (A-3) with allyl isomerization catalystin an organic solvent or mixture of water and a water miscible organicsolvent; at a temperature of in the range of from about 75° C. to about105° C.; to yield the corresponding compound of formula (A-4), whereinthe compound of formula (A-4) is not isolated;

reacting the compound of formula (A-4) with an co-oxidant; in thepresence of an oxidizing reagent; in an organic solvent or mixture ofwater and a water miscible organic solvent; at a temperature in therange of from about 0° C. to about 50° C.; to yield the correspondingcompound of formula (A-5);

reacting the compound of formula (A-5) under SWERN oxidation conditions;to yield the corresponding compound of formula (V-S)

The present invention is further directed to processes for thepreparation of the compounds of formula (I). The present invention isfurther directed to a product prepared according to any of theprocess(es) described herein.

Illustrative of the invention are pharmaceutical compositions comprisinga pharmaceutically acceptable carrier and a compound of formula (I) asdescribed herein. An illustration of the invention is a pharmaceuticalcomposition made by mixing a compound of formula (I) as described hereinand a pharmaceutically acceptable carrier. Illustrating the invention isa process for making a pharmaceutical composition comprising mixing acompound of formula (I) as described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods of treating a disease, disorder,or condition mediated by SGLT activity (preferably, dual SGLT1 and SGLT2activity) selected from the group consisting of impaired glucosetolerance (IGT), impaired fasting glucose (IFT), gestational diabetes,Type II diabetes mellitus, Syndrome X (also known as MetabolicSyndrome), obesity, nephropathy, neuropathy, retinopathy, hypertension,angina, atherosclerosis, heart disease, heart attack, ischemia, stroke,nerve damage or poor blood flow in the feet, non-alcoholicsteatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liverfibrosis, cataracts, polycystic ovarian syndrome, irritable bowelsyndrome, inflammation and cancer (preferably prostate cancer orpancreatic cancer), comprising administering to a subject in needthereof a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

In an embodiment, the present invention is directed to a compound offormula (I) for use as a medicament. In another embodiment, the presentinvention is directed to a compound of formula (I) for use in thetreatment of a disorder mediated SGLT activity (preferably dual SGLT1and SGLT2 activity) selected from the group consisting impaired glucosetolerance (IGT), impaired fasting glucose (IFT), gestational diabetes,Type II diabetes mellitus, Syndrome X (also known as MetabolicSyndrome), obesity, nephropathy, neuropathy, retinopathy, hypertension,angina, atherosclerosis, heart disease, heart attack, ischemia, stroke,nerve damage or poor blood flow in the feet, non-alcoholicsteatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liverfibrosis, cataracts, polycystic ovarian syndrome, irritable bowelsyndrome, inflammation and cancer (preferably prostate cancer orpancreatic cancer). In another embodiment, the present invention isdirected to a composition comprising a compound of formula (I) for thetreatment of a disorder mediated by SGLT activity (preferably dual SGLT1and SGLT2 activity) selected from the group consisting impaired glucosetolerance (IGT), impaired fasting glucose (IFT), gestational diabetes,Type II diabetes mellitus, Syndrome X (also known as MetabolicSyndrome), obesity, nephropathy, neuropathy, retinopathy, hypertension,angina, atherosclerosis, heart disease, heart attack, ischemia, stroke,nerve damage or poor blood flow in the feet, non-alcoholicsteatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liverfibrosis, cataracts, polycystic ovarian syndrome, irritable bowelsyndrome, inflammation and cancer (preferably prostate cancer orpancreatic cancer).

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)impaired glucose tolerance (IGT), (b) impaired fasting glucose (IFT),(c) gestational diabetes, (d) Type II diabetes mellitus, (e) Syndrome X(also known as Metabolic Syndrome), (f) obesity, (g) nephropathy, (h)neuropathy, (i) retinopathy, (j) hypertension, (k) angina, (I)atherosclerosis, (m) heart disease, (n) heart attack, (o) ischemia, (p)stroke, (q) nerve damage or poor blood flow in the feet, (r)non-alcoholic steatohepatitis (NASH), (s) non-alcoholic fatty liverdisease (NAFLD), (t) liver fibrosis, (u) cataracts, (v) polycysticovarian syndrome, (w) irritable bowel syndrome, (x) inflammation and (y)cancer (preferably prostate cancer or pancreatic cancer), in a subjectin need thereof. In another example, the present invention is directedto a compound as described herein for use in a methods for treating adisorder selected from the group consisting of impaired glucosetolerance (IGT), impaired fasting glucose (IFT), gestational diabetes,Type II diabetes mellitus, Syndrome X (also known as MetabolicSyndrome), obesity, nephropathy, neuropathy, retinopathy, hypertension,angina, atherosclerosis, heart disease, heart attack, ischemia, stroke,nerve damage or poor blood flow in the feet, non-alcoholicsteatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liverfibrosis, cataracts, polycystic ovarian syndrome, irritable bowelsyndrome, inflammation and cancer (preferably prostate cancer orpancreatic cancer), in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein R¹, R², R³, R⁴, R⁵, R⁶ and

are as herein defined; and isotopologues and pharmaceutically acceptablesalts thereof. The compounds of the present invention are useful in thetreatment of diseases, disorders and complications associated with SGLTactivity (preferably dual SGLT1 and SGLT2 activity) selected from thegroup of impaired glucose tolerance (IGT), impaired fasting glucose(IFT), gestational diabetes, Type II diabetes mellitus, Syndrome X (alsoknown as Metabolic Syndrome), obesity, nephropathy, neuropathy,retinopathy, hypertension, angina, atherosclerosis, heart disease, heartattack, ischemia, stroke, nerve damage or poor blood flow in the feet,non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease(NAFLD), liver fibrosis, cataracts, polycystic ovarian syndrome,irritable bowel syndrome, inflammation and cancer (preferably prostatecancer or pancreatic cancer).

In an embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of—C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, —CH₂—R¹⁰, C₃₋₆cycloalkyl,hydroxy substituted C₃₋₆cycloalkyl and —C(O)OH; wherein R¹⁰ is selectedfrom the group consisting of fluoro, C₁₋₂alkoxy, cyano and NR^(A)R^(B);wherein R^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and C₁₋₂alkyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R¹ is selectedfrom the group consisting of —C₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl,—CH₂—R¹⁰, hydroxy substituted C₃₋₆cycloalkyl and —C(O)OH; wherein R¹⁰ isselected from the group consisting of fluoro, C₁₋₂alkoxy, cyano andamino.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of methyl-,fluoro-methyl-, cyano-methyl-, amino-methyl-, hydroxy-methyl-,methoxy-methyl-, 1R-hydroxy-ethyl-, 1 S-hydroxy-ethyl-,1-hydroxy-isopropyl, 1-hydroxy-cyclopro-1-yl and carboxy. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R¹ is selected from the group consisting of methyl-,fluoro-methyl-, cyano-methyl-, hydroxy-methyl-, 1R-hydroxy-ethyl- and1S-hydroxy-ethyl-. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R¹ is selected from thegroup consisting of hydroxy-methyl- and 1R-hydroxy-ethyl-. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R¹ is hydroxy-methyl- (i.e. —CH₂—OH).

In an embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, halogen, hydroxy, C₁₋₄alkyl, —(C₁₋₄alkyl)-OH, C₁₋₄alkoxy,cyano substituted C₁₋₂alkoxy, C₂₋₄alkenyl-oxy-, benzyloxy- and carboxy.In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, halogen, hydroxy, C₁₋₂alkyl, —(C₁₋₄alkyl)-OH, C₁₋₂alkoxy,cyano substituted C₁₋₂alkoxy, C₂₋₃alkenyl-oxy-, benzyloxy- and carboxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, chloro, fluoro, hydroxy, methyl, hydroxy-methyl-, methoxy,tri-deutero-methoxy, cyano-methoxy-, ethoxy, propen-2-yl-oxy, benzyloxyand carboxy. In another embodiment, the present invention is directed tocompounds of formula (I) wherein R² is selected from the groupconsisting of hydrogen, chloro, fluoro, hydroxy, hydroxy-methyl-,methoxy, tri-deutero-methoxy, cyano-methoxy-, ethoxy, propen-2-yl-oxy,benzyloxy and carboxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, hydroxy, methyl, methoxy, benzyloxy and tri-deutero-methoxy.In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting ofhydrogen, fluoro, hydroxy, methyl, hydroxy-methyl-, methoxy,tri-deutero-methoxy and ethoxy. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R² is selectedfrom the group consisting of hydrogen, hydroxy, methyl, hydroxy-methyl-,methoxy, ethoxy and tri-deutero-methoxy. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein R² isselected from the group consisting of hydrogen, hydroxy, methoxy andethoxy. In another embodiment, the present invention is directed tocompounds of formula (I) wherein R² is selected from the groupconsisting of hydroxy, methoxy and ethoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting of hydroxyand methoxy.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R³ is selected from the group consisting ofhydrogen, halogen, C₁₋₄alkyl and C₂₋₄alkenyl. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein R³ isselected from the group consisting of hydrogen, halogen, C₁₋₂alkyl andC₂₋₃alkenyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R³ is selected from the group consisting ofhydrogen, fluoro, methyl and n-propen-2-yl. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein R³ isselected from the group consisting of hydrogen and methyl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R³ is hydrogen;

In an embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofhydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₂alkyl,C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy, and C₃₋₆cycloalkyl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R⁴ is selected from the group consisting of hydrogen,halogen, hydroxy, C₁₋₂alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy,fluorinated C₁₋₂alkoxy, cyano and C₃₋₆cycloalkyl;

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofhydrogen, chloro, fluoro, hydroxy, methyl, ethyl, trifluoromethyl,methoxy, ethoxy, isopropyloxy, trifluoromethoxy, cyano and cyclopropyl.In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofhydrogen, chloro, fluoro, methyl, ethyl, trifluoromethyl, methoxy,ethoxy, isopropyloxy, trifluoromethoxy, cyano and cyclopropyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting of hydroxy,chloro, methyl, ethyl, methoxy and ethoxy. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein R⁴ isselected from the group consisting of chloro, methyl, ethyl, methoxy andethoxy. In another embodiment, the present invention is directed tocompounds of formula (I) wherein R⁴ is selected from the groupconsisting of hydroxy, chloro, methyl, ethyl, methoxy, and cyclopropyl.In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting of chloro,methyl, ethyl and methoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is methoxy.

In certain embodiments, the present invention is directed to compoundsof formula (I) wherein the

is selected from the group consisting of

(such that —R²—R³— is selected from the group consisting of —O—CH₂—CH₂—and —CH₂—CH₂—O; and —R³—R⁴— is selected from the group consisting of—CH₂—CH₂—O— and —O—CH₂—CH₂—, respectively); and wherein the2,3-dihydrofuranyl portion of the structure is optionally substituted asherein defined.

In certain embodiments, the present invention is directed to compoundsof formula (I) wherein the

is selected from the group consisting of

and wherein the 2,3-dihydrofuranyl portion of the structure isoptionally substituted as herein defined. In certain embodiments, thepresent invention is directed to compounds of formula (I) wherein the

is selected from the group consisting of

and wherein the 2,3-dihydrofuranyl portion of the structure isoptionally substituted as herein defined.

In certain embodiments, the present invention is directed to compoundsof formula (I) wherein the

(such that —R²—R³— is —O—CH₂—CH₂—); and wherein the 2,3-dihydrofuranylportion of the structure is optionally substituted as herein defined. Incertain embodiments, the present invention is directed to compounds offormula (I) wherein the

(such that —R²—R³— is —CH₂—CH₂—O—); and wherein the 2,3-dihydrofuranylportion of the structure is optionally substituted as herein defined. Incertain embodiments, the present invention is directed to compounds offormula (I) wherein the

such that —R³—R⁴— is —CH₂—CH₂—O—); and wherein the 2,3-dihydrofuranylportion of the structure is optionally substituted as herein defined. Incertain embodiments, the present invention is directed to compounds offormula (I) wherein the

(such that —R³—R⁴— is —O—CH₂—CH₂—); and wherein the 2,3-dihydrofuranylportion of the structure is optionally substituted as herein defined.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R² and R³ or R³ and R⁴ are taken together with thecarbon atoms to which they are bound to form a ring structure selectedfrom the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl; wherein the 2,3-dihydrofuranyl is optionallysubstituted as herein defined.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R² and R³ or R³ and R⁴ are taken together with thecarbon atoms to which they are bound to form 2,3-dihydro-furanyl;wherein the 2,3-dihydro-furanyl is optionally substituted with one tothree substituent independently selected from the group consisting ofmethyl, ethyl, hydroxy-methyl- and hydroxy-ethyl-. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R² and R³ or R³ and R⁴ are taken together with the carbonatoms to which they are bound to form 2,3-dihydro-furanyl; wherein the2,3-dihydro-furanyl, is optionally substituted with one to threesubstituent independently selected from the group consisting of methyl,hydroxy-methyl- and hydroxy-ethyl-.

In another embodiment, the present invention is directed to compounds offormula (I) wherein, R² and R³ or R³ and R⁴ are taken together with thecarbon atoms to which they are bound to form a ring structure selectedfrom the group consisting of 2,3-dihydro-furanyl,3-hydroxy-methyl-2,3-dihydro-furanyl,3-hydroxy-ethyl-2,3-dihydro-furanyl,3-hydroxy-methyl-2,2-dimethyl-2,3-dihydro-furanyl,3-methyl-2,3-dihydro-furanyl and3-methyl-3-hydroxy-methyl-2,3-dihydro-furanyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein alternatively, R² and R³ or R³ and R⁴ are takentogether with the carbon atoms to which they are bound to form2,3-dihydro-furanyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R² and R³ are taken together with the carbon atomsto which they are bound to form 2,3-dihydro-furanyl, wherein the2,3-furanyl is optionally substituted as herein defined. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R² and R³ are taken together with the carbon atoms to whichthey are bound to form 2,3-dihydro-furanyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R³ and R⁴ are taken together with the carbon atomsto which they are bound to form 2,3-dihydro-furanyl, wherein the2,3-dihydro-furanyl is optionally substituted as herein defined.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R³ and R⁴ are taken together with the carbon atomsto which they are bound to form a ring structure selected from the groupconsisting of 2,3-dihydro-furanyl,3-hydroxy-2,2-dimethyl-2,3-dihydro-furanyl,3-hydroxymethyl-2,3-dihydro-furanyl, 3-hydroxyethyl-2,3-dihydro-furanyl,3-methyl-3-hydroxymethyl-2,3-dihydro-furanyl and3-methyl-2,3-dihydro-furanyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R³ and R⁴ are taken together with the carbon atomsto which they are bound to form 2,3-dihydro-furanyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein R⁵ and R⁶ are the same and are hydrogen. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R⁵ and R⁶ are the same and are selected from the groupconsisting of hydrogen and deuterium.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of C₅₋₁₂cycloalkyl,C₅₋₁₂cycloalkenyl, phenyl, heteroaryl and heterocyclyl; wherein thephenyl, heteroaryl or heterocyclyl is optionally substituted with one totwo substituent independently selected from the group consisting ofhalogen, hydroxy, oxo, C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy,cyano, 2,5-dimethyl-thien-3-yl, 5-methyl-thiazol-2-yl and —C(O)—R¹¹; andwherein R¹¹ is selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, C₃₋₆cycloalkyl, azetidin-1-yl, pyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, morpholin-4-yl and thiazol-2-yl. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of C₅₋₁₂cycloalkyl,C₅₋₁₂cycloalkenyl, phenyl, heteroaryl and heterocyclyl; wherein thephenyl is optionally substituted with one substituent independentlyselected from the group consisting of halogen, C₁₋₂alkyl, C₁₋₂alkoxy andfluorinated C₁₋₂alkoxy; wherein the heteroaryl or heterocyclyl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₂alkyl, oxo, cyano,2,5-dimethyl-thien-3-yl, 5-methyl-thiazol-2-yl and —C(O)—R¹¹; andwherein R¹¹ is selected from the group consisting of C₁₋₂alkyl,C₁₋₂alkoxy, C₃₋₆cycloalkyl, pyrrolidin-1-yl, morpholin-4-yl andthiazol-2-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of 4-chloro-phenyl,4-ethyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl,4-(fluoro-methoxy)-phenyl, chroman-6-yl, benzothien-2-yl,3,4-dihydro-2H-quinolin-7-yl, 1-methyl-3,4-dihydro-2H-quinolin-7-yl,benzo[b][1,4]oxazin-7-yl-3-one, 6,7-dihydrobenzo[b]thiophen-2-yl-4-one,2,2-difluoro-benzo[d][1,3]dioxol-5-yl,2,3-dihydro-benzo[b][1,4]dioxin-6-yl,2,3-dihydrobenzo[b][1,4]oxathiin-6-yl, bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, 6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl,5,6-dihydro-7H-thieno[3,2-b]pyran-2-yl-7-one,5-(5-methyl-thiazol-2-yl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(2,5-dimethyl-thien-3-yl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-methyl-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-methoxy-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-ethoxy-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-cyano-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(cyclopentyl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(pyrrolidin-1-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(morpholin-4-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(thiazol-2-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,3,3-dideutero-2,3-dihydrobenzo[b][1,4]dioxin-6-yl and2,2,3,3-tetra-deutero-2,3-dihydrobenzo[b][1,4]dioxin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of chroman-6-yl, benzothien-2-yl,6,7-dihydrobenzo[b]thiophen-2-yl-4-one,2,2-difluoro-benzo[d][1,3]dioxol-5-yl,2,3-dihydro-benzo[b][1,4]dioxin-6-yl,bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl,6,7-dihydro-5H-thieno[3,2-b]pyran-2-yl,5,6-dihydro-7H-thieno[3,2-b]pyran-2-yl-7-one,5-(5-methyl-thiazol-2-yl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(2,5-dimethyl-thien-3-yl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-methyl-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-methoxy-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-ethoxy-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-cyano-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(cyclopentyl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(pyrrolidin-1-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(morpholin-4-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(thiazol-2-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl and2,2,3,3-tetra-deutero-2,3-dihydrobenzo[b][1,4]dioxin-6-yl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein

is selected from the group consisting of benzothien-2-yl, chroman-6-yl,2,3-dihydro-benzo[b][1,4]dioxin-6-yl,2,3-dihydro-benzo[b][1,4]oxathiin-6-yl, bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, 3,3-dideutero-2,3-dihydro-benzo[b][1,4]dioxin-6-yland 2,2,3,3-tetradeutero-2,3-dihydro-benzo[b][1,4]dioxin-6-yl. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of 4-ethyl-phenyl,4-ethoxy-phenyl, 4-(fluoro-methoxy)-phenyl, benzothien-2-yl,chroman-6-yl, 2,3-dihydro-benzo[b][1,4]dioxin-6-yl,3,4-dihydro-quiunolin-7-yl, 1-methyl-3,4-dihydro-quinolin-7-yl,benzo[b][1,4]oxazin-7-yl-3-one, 2,3-dihydro-benzo[b][1,4]oxathiin-6-yl,5-(pyrrolidin-1-yl-carbonyl)-6,7-dihydro-thieno[3,2-c]pyridin-2-yl and2,2,3,3-tetradeutero-2,3-dihydro-benzo[b][1,4]dioxin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of 4-ethyl-phenyl,4-ethoxy-phenyl, 4-(fluoro-methoxy)-phenyl, chroman-6-yl,benzothien-2-yl, 3,4-dihydro-2H-quinolin-7-yl,1-methyl-3,4-dihydro-2H-quinolin-7-yl,6,7-dihydrobenzo[b]thiophen-2-yl-4-one,2,3-dihydro-benzo[b][1,4]dioxin-6-yl,2,3-dihydrobenzo[b][1,4]oxathiin-6-yl, bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, 5,6-dihydro-7H-thieno[3,2-b]pyran-2-yl-7-one,5-(5-methyl-thiazol-2-yl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-methoxy-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-ethoxy-carbonyl-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-cyano-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(cyclopentyl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(pyrrolidin-1-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,5-(thiazol-2-yl-carbonyl)-6,7-dihydrothieno[3,2-c]pyridin-2-yl,3,3-dideutero-2,3-dihydrobenzo[b][1,4]dioxin-6-yl and2,2,3,3-tetra-deutero-2,3-dihydrobenzo[b][1,4]dioxin-6-yl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein

is selected from the group consisting of 4-ethyl-phenyl,4-ethoxy-phenyl, 4-(fluoro-methoxy)-phenyl, benzothien-2-yl,3,4-dihydro-2H-quinolin-7-yl, 2,3-dihydro-benzo[b][1,4]dioxin-6-yl,2,3-dihydrobenzo[b][1,4]oxathiin-6-yl, bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, 5,6-dihydro-7H-thieno[3,2-b]pyran-2-yl-7-one,5-cyano-6,7-dihydrothieno[3,2-c]pyridin-2-yl and2,2,3,3-tetra-deutero-2,3-dihydrobenzo[b][1,4]dioxin-6-yl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein

is selected from the group consisting of 4-ethyl-phenyl,4-ethoxy-phenyl, benzothien-2-yl, 2,3-dihydro-benzo[b][1,4]dioxin-6-yl,bicyclo[4.2.0]octa-1 (6),2,4-trien-3-yl and5-cyano-6,7-dihydrothieno[3,2-c]pyridin-2-yl. In another embodiment, thepresent invention is directed to compounds of formula (I) wherein

is selected from the group consisting of5-cyano-6,7-dihydro-thieno[3,2-c]pyridin-2-yl,bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl and2,3-dihydro-benzo[b][1,4]dioxin-6-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of C₅₋₁₂cycloalkyl,C₅₋₁₂cycloalkenyl, heteroaryl and heterocyclyl; wherein the phenyl,heteroaryl or heterocyclyl is optionally substituted as herein defined.In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of heteroaryl and heterocyclyl;wherein the heteroaryl or heterocyclyl is optionally substituted asherein defined. In another embodiment, the present invention is directedto compounds of formula (I) wherein

is selected from the group consisting of C₅₋₁₂cycloalkyl andC₅₋₁₂cycloalkenyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is selected from the group consisting of2,3-dihydro-benzo[b][1,4]-dioxin-6-yl and 2,2,3,3-tetradeutero- of2,3-dihydro-benzo[b][1,4]-dioxin-6-yl.

In an embodiment, the present invention is directed to a compound offormula (I) selected from the group consisting of

-   (2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol    (Compound #65);-   (2S,3R,4R,5S,6R)-2-[5-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol    (Compound #101);-   (2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol    (Compound #61);-   (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-[4-methoxy-7-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)methyl]-2,3-dihydrobenzofuran-5-yl]tetrahydropyran-3,4-diol    (Compound #172);-   (2S,3R,4R,5S,6R)-2-[7-[dideuterio(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-methoxy-2,3-dihydrobenzofuran-5-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol    (Compound #163);

and isotopologues and pharmaceutically acceptable salts thereof.

In an embodiment, the present invention is directed to compounds offormula (I) wherein

is other than phenyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein

is other than thienyl or pyridyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein

is other than benzothien-2-yl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein

is other than thienyl or pyridyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein

is other than phenyl, thienyl or pyridyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

is other than phenyl, thienyl, furyl, pyridyl, pyrrolyl, imidazolyl,thioimidazolyl, oxazolyl, pyrimidinyl, pyrrolidinyl, naphthyl,benzofuryl, benzothienyl, benzothiazolyl, benzopyrazolyl, benzoxazolyl,indolyl or quinolinyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein when

is phenyl, then then R² and R³ or R³ and R⁴ are taken together with thecarbon atoms to which they are bound to form a ring structure selectedfrom the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein when

is thien-2-yl or pyridyl, then R² and R³ or R³ and R⁴ are taken togetherwith the carbon atoms to which they are bound to form a ring structureselected from the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein when

is benzothien-2-yl, then R² and R³ or R³ and R⁴ are taken together withthe carbon atoms to which they are bound to form a ring structureselected from the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl. In another embodiment, the present invention isdirected to compounds of formula (I) wherein when

is thienyl, pyridyl or benzothien-2-yl, then R² and R³ or R³ and R⁴ aretaken together with the carbon atoms to which they are bound to form aring structure selected from the group consisting of 2,3-dihydrofuranyland 3,4-dihydro-2H-pyranyl. In another embodiment, the present inventionis directed to compounds of formula (I) wherein when

is phenyl, thienyl, pyridyl or benzothien-2-yl, then R² and R³ or R³ andR⁴ are taken together with the carbon atoms to which they are bound toform a ring structure selected from the group consisting of2,3-dihydrofuranyl and 3,4-dihydro-2H-pyranyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is hydroxy-methyl-, R² is hydrogen, R³ ishydrogen, R⁴ is hydrogen or chloro, R⁵ is hydrogen, R⁶ is hydrogen and

is other than benzothien-2-yl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R¹ ishydroxy-methyl-, R² is hydrogen, R³ is hydrogen, R⁴ is chloro, R⁵ ishydrogen, R⁶ is hydrogen and

is other than benzothien-2-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is hydroxy-methyl-, R² is hydrogen, R³ ishydrogen, R⁴ is hydrogen or chloro, R⁵ is hydrogen, R⁶ is hydrogen and

is other than benzothien-2-yl, thien-2-yl or indol-3-yl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R¹ is hydroxy-methyl-, R² is hydrogen, R³ is hydrogen, R⁴ ischloro, R⁵ is hydrogen, R⁶ is hydrogen and

is other than benzothien-2-yl, thien-2-yl or indol-3-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein when

is phenyl, thienyl, furyl, pyridyl, pyrrolyl, imidazolyl,thioimidazolyl, oxazolyl, pyrimidinyl, pyrrolidinyl, naphthyl,benzofuryl, benzothienyl, benzothiazolyl, benzopyrazolyl, benzoxazolyl,indolyl or quinolinyl then R² and R³ or R³ and R⁴ are taken togetherwith the carbon atoms to which they are bound to form a ring structureselected from the group consisting of 2,3-dihydrofuranyl and3,4-dihydro-2H-pyranyl.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R², R³, R⁴, R⁵, R⁶,

, etc.) are independently selected to be any individual substituent orany subset of substituents selected from the complete list as definedherein. Additional embodiments of the present invention, include thosewherein the substituents selected for one or more of the variablesdefined herein (i.e. R¹, R², R³, R⁴, R⁵, R⁶,

, etc.) are independently selected to correspond to any of theembodiments as defined herein.

In another embodiment of the present invention is any single compound orsubset of compounds selected from the representative compounds listed inTables 1 to 3 below.

Representative compounds of the present invention are as listed in Table1 to 3 below. Unless otherwise noted, wherein a stereogenic center ispresent in the listed compound, the compound was prepared as a mixtureof stereo-configurations. Where a stereogenic center is present, the S*-and R* designations are intended to indicate that the exactstereo-configuration of the center has not been determined.

TABLE 1 Representative Compounds Formula (I)

ID No. R¹ R² R³ R⁴ R⁵ R⁶

2 CH₂— hydroxy H me- H H benzothien-2-yl OH thoxy 4 CH₂— hydroxy Hmethyl H H benzothien-2-yl OH 7 CH₂— hydroxy H chloro H Hbenzothien-2-yl OH 9 CH₂— hydroxy H me- H H benzothien-2-yl OCH₃ thoxy10 CH₃ hydroxy H me- H H benzothien-2-yl thoxy 11 CH₂F hydroxy H me- H Hbenzothien-2-yl thoxy 12 CH₂— methoxy H me H H benzothien-2-yl OH thoxy-13 CH₂— hydroxy methyl methyl H H benzothien-2-yl OH 14 CH₂— hydroxymethyl me- H H benzothien-2-yl OH thoxy 15 CH₂— methoxy methyl me- H Hbenzothien-2-yl OH thoxy 16 CH₃ hydroxy H methyl H H benzothien-2-yl 18CH₂— methoxy H methyl H H benzothien-2-yl OH 19 CH₂— hydroxy H methyl HH benzothien-2-yl OCH₃ 20 CH₂F hydroxy H methyl H H benzothien-2-yl 21CH₂— chloro H me- H H benzothien-2-yl OH thoxy 22 CH₂— hydroxy H me- H Hbenzothien-2-yl CN thoxy 23 CH₂— hydroxy H methyl H H benzothien-2-yl CN24 CH₂— hydroxy H methyl H H benzothien-2-yl NH₂ 26 CH₂— chloro H me- HH benzothien-2-yl CN thoxy 28 CH₂— hydroxy H me- H H benzothien-2-yl NH₂thoxy 29 CH₂— hydroxy H cyclo- H H benzothien-2-yl OH propyl 30 CH₂—hydroxy H ethoxy H H benzothien-2-yl OH 31 CH₂— hydroxy H ethyl H Hbenzothien-2-yl OH 32 CH₂— hydroxy H iso- H H benzothien-2-yl OH propyl-oxy 33 CH₂— hydroxy H cyano H H benzothien-2-yl OH 34 CH₂— hydroxy- Hme- H H benzothien-2-yl OH methyl- thoxy 35 CH₂— methoxy H chloro H Hbenzothien-2-yl OH 36 CH₂— hydroxy H fluoro H H benzothien-2-yl OH 37CH(R*— hydroxy H methyl H H benzothien-2-yl OH)— CH₃ 38 CH(S*— hydroxy Hmethyl H H benzothien-2-yl OH)— CH₃ 39 C(OH)— hydroxy H methyl H Hbenzothien-2-yl (CH₃)₂ 40 CH₂— carboxy H me- H H benzothien-2-yl OHthoxy 41 CH₂— hydroxy H tri- H H benzothien-2-yl OH fluoro- methyl 42CH₂— hydroxy- H methyl H H benzothien-2-yl OH methyl- 43 1-OH— hydroxy Hmethyl H H benzothien-2-yl cyclo- prop-1- yl 44 C(O) hydroxy H methyl HH benzothien-2-yl OH 46 1-OH— hydroxy H me- H H benzothien-2-yl cyclo-thoxy prop-1- yl 47 CH₂— benzyl- H me- H H benzothien-2-yl OH oxy thoxy48 C(OH)— hydroxy H me- H H benzothien-2-yl (CH₃)₂ thoxy 49 CH₂—propen-2- H me- H H benzothien-2-yl OH yl-oxy thoxy 50 CH₂— hydroxy Htri- H H benzothien-2-yl OH fluoro- me- thoxy 51 C(O) hydroxy H me- H Hbenzothien-2-yl OH thoxy 52 C(R*— hydroxy H me- H H benzothien-2-ylOH)CH₃ thoxy 53 C(S*— hydroxy H me- H H benzothien-2-yl OH)CH₃ thoxy 55CH₂— H H me- H H 6,7-dihydro-5H- OH thoxy thieno[3,2- b]pyran-2-yl 57C(OH)— hydroxy H ethyl H H benzothien-2-yl (CH₃)₂ 64 CH₂— hydroxy Hmethyl H H 5-ethoxy- OH carbonyl-6,7- dihydrothieno[3, 2-c]pyridin-2-yl66 CH₂— hydroxy H methyl H H 5-(pyrrolidin-1- OH yl-carbonyl)-6,7-dihydrothieno[3- 2-c]pyridin-2-yl 67 CH₂— hydroxy H methyl H H5-(morpholin-4- OH yl-carbonyl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl69 CH₂— methoxy H methyl H H 5-(morpholin-4- OH yl-carbonyl)-6,7-dihydrothieno[3, 2-c]pyridin-2-yl 71 C(R*— cyano- H me- H Hbenzothien-2-yl OH)CH₃ methoxy- thoxy 72 C(R*— methoxy H me- H Hbenzothien-2-yl OH)CH₃ thoxy 73 CH₂— hydroxy H chloro H H 5-methoxy- OHcarbonyl-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 74 CH₂— hydroxy H chloroH H 5-methyl- OH carbonyl-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 76 CH₂—methoxy H chloro H H 5-methoxy- OH carbonyl-6,7- dihydrothieno[3,2-c]pyridin-2-yl 77 CH₂— methoxy H chloro H H 5-methyl- OH carbonyl-6,7-dihydrothieno[3, 2-c]pyridin-2-yl 78 CH₂— H H methyl H H5-(pyrrolidin-1- OH yl-carbonyl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl79 CH₂— hydroxy H me- H H 5-methyl- OH thoxy carbonyl-6,7-dihydrothieno[3, 2-c]pyridin-2-yl 80 CH₂— H H chloro H H 5-methoxy- OHcarbonyl-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 81 CH₂— methoxy H methylH H 5-(pyrrolidin-1- OH yl-carbonyl)-6,7- dihydrothieno[3,2-c]pyridin-2-yl 82 CH₂— methoxy H me- H H 5-methyl- OH thoxycarbonyl-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 83 CH₂— methoxy H me- HH 5-methoxy- OH thoxy carbonyl-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 84CH₂— hydroxy H methyl H H 5-(thiazol-2-yl- OH carbonyl)-6,7-dihydrothieno[3, 2-c]pyridin-2-yl 86 CH₂— hydroxy H methyl H H5-(cyclopentyl- OH carbonyl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 87CH₂— H H methyl H H 5-(cyclopentyl- OH carbonyl)-6,7- dihydrothieno[3,2-c]pyridin-2-yl 90 CH₂— H n- me- H H benzothien-2-yl OH propen- thoxy2-yl 91 CH₂— methoxy H methyl H H 5-(cyclopentyl- OH carbonyl)-6,7-dihydrothieno[3, 2-c]pyridin-2-yl 92 CH₂— H H methyl H H 5-cyano-6,7- OHdihydrothieno[3, 2-c]pyridin-2-yl 96 CH₂— methoxy H chloro H H5-(pyrrolidin-1- OH yl-carbonyl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl99 CH₂— methoxy H chloro H H 5-cyano-6,7- OH dihydrothieno[3,2-c]pyridin-2-yl 100 CH₂— hydroxy H me- H H 5-cyano-6,7- OH thoxydihydrothieno[3, 2-c]pyridin-2-yl 103 CH₂— hydroxy H methyl H H5-cyano-6,7- OH dihydrothieno[3, 2-c]pyridin-2-yl 104 CH₂— methoxy H me-H H 5-cyano-6,7- OH thoxy dihydrothieno[3, 2-c]pyridin-2-yl 106 CH₂—methoxy H chloro H H 5-(thiazol-2-yl- OH carbonyl)-6,7- dihydrothieno[3,2-c]pyridin-2-yl 109 CH₂— H H methyl H H 5-(thiazol-2-yl- OHcarbonyl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 110 CH₂— methoxy Hmethyl H H 5-cyano-6,7- OH dihydrothieno[3, 2-c]pyridin-2-yl 111 CH₂—hydroxy H methyl H H 5-(5-methyl- OH thiazol-2-yl)-6,7- dihydrothieno[3,2-c]pyridin-2-yl 112 CH₂— methoxy H methyl H H 5-(thiazol-2-yl- OHcarbonyl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 113 CH₂— H H methyl H H5-(5-methyl- OH thiazol-2-yl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 114CH₂— hydroxy H chloro H H 5-cyano-6,7- OH dihydrothieno[3,2-c]pyridin-2-yl 115 CH₂— methoxy H ethyl H H 5-cyano-6,7- OHdihydrothieno[3, 2-c]pyridin-2-yl 116 CH₂— H H methyl H H 6,7- OHdihydrobenzo[b] thiophen-2-yl-4- one 117 CH₂— hydroxy H methyl H H5-(5-methyl- OH thiazol-2-yl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 118CH₂— hydroxy H ethyl H H 5-cyano-6,7- OH dihydrothieno[3,2-c]pyridin-2-yl 119 CH₂— hydroxy H methyl H H 6,7- OH dihydrobenzo[b]thiophen-2-yl-4- one 120 CH₂— H H me- H H 5-cyano-6,7- OH thoxydihydrothieno[3, 2-c]pyridin-2-yl 121 CH₂— H H chloro H H 5-cyano-6,7-OH dihydrothieno[3, 2-c]pyridin-2-yl 122 CH₂— H H methyl H H5-(5-methyl- OH thiazol-2-yl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl 123CH₂— methoxy H methyl H H 5-(5-methyl- OH thiazol-2-yl)-6,7-dihydrothieno[3, 2-c]pyridin-2-yl 129 CH₂— hydroxy H methyl H H5,6-dihydro-7H- OH thieno[3,2- b]pyran-2-yl-7- one 138 CH₂— H H methyl HH 5-(2,5-dimethyl- OH thien-3-yl)-6,7- dihydrothieno[3, 2-c]pyridin-2-yl156 CH₂— H H ethyl D D 2,3-dihydro- OH benzo[b][1,4] dioxin-6-yl 157CH₂— H H ethyl D D 2,3-dihydro- OH benzo[b][1,4] dioxin-6-yl 158 CH₂— HH ethyl H H 2,2-difluoro- OH benzo[b][1,3] dioxol-5-yl 159 CH₂— H Hethyl H H 2,2-difluoro- OH benzo[b][1,3] dioxol-5-yl 165 CH₂— fluoro Hme- D D 2,3-dihydro- OH thoxy benzo[b][1,4] dioxin-6-yl 166 CH₂— H Hchloro D D 2,3-dihydro- OH benzo[b][1,4] dioxin-6-yl 167 CH₂— H H methylD D 2,3-dihydro- OH benzo[b][1,4] dioxin-6-yl 169 CH₂— H H ethyl D Dchroman-6-yl OH 171 CH₂— H H me- D D chroman-6-yl OH thoxy 173 CH₂— H Hme- H H 2,2,3,3-tetra- OH thoxy deutero-2,3- dihydrobenzo[b][1,4]dioxin-6-yl 175 CH₂— H H ethyl H H 2,2,3,3-tetra- OH deutero-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl 176 CH₂— H H ethyl D D 2,2,3,3-tetra-OH deutero-2,3- dihydrobenzo[b] [1,4]dioxin-6-yl 178 CH₂— H fluoro me- HH 2,2,3,3-tetra- OH thoxy deutero-2,3- dihydrobenzo[b] [1,4]dioxin-6-yl182 CH₂— OCD₃ H ethyl H H 2,3-dihydro- OH benzo[b][1,4] dioxin-6-yl

TABLE 2 Representative Compounds of Formula (I) wherein R² and R³ aretaken together to form a ring structure

ID —R²—R³— No. R¹ together R⁴ R⁵ R⁶

68 CH₂— —O—CH₂— methyl H H benzothien-2-yl OH CH₂— 98 CH₂— —O—CH₂—hydroxy H H 2,3-dihydro- OH CH₂  benzo[b][1,4]dioxin- 6-yl 101 CH₂——O—CH₂— methoxy H H 2,3-dihydro- OH CH₂  benzo[b][1,4]dioxin- 6-yl 102CH₂— —O—CH₂— ethoxy H H 2,3-dihydro- OH CH₂  benzo[b][1,4]dioxin- 6-yl125 CH₂— —O—CH₂— chloro H H chroman-6-yl OH CH₂  126 CH₂— —O—CH₂—methoxy H H chroman-6-yl OH CH₂  127 CH₂— —O—CH₂— chloro H H 2,3- OHCH₂  dihydrobenzo[b][1,4] oxathiin-6-yl 128 CH₂— —O—CH₂— methoxy H H2,3- OH CH₂  dihydrobenzo[b][1,4] oxathiin-6-yl 130 CH₂— —O—CH₂— methylH H chroman-6-yl OH CH₂  132 CH₂— —O—CH₂— methyl H H 2,3- OH CH₂ dihydrobenzo[b][1,4] oxathiin-6-yl 152 CH₂— —O—CH₂— methoxy H Hbicyclo[4.2.0]octa- OH CH₂  1(6),2,4-trien-3-yl 154 CH₂— —CH₂—CH₂—chloro H H 2,3-dihydro- OH O  benzo[b][1,4]dioxin- 6-yl 179 CH₂— —O—CH₂—ethyl H H 2,2,3,3-tetra- OH CH₂  deutero-2,3- dihydrobenzo[b][1,4]dioxin-6-yl 180 CH₂— —O—CH₂— ethyl H H 3,3-dideutero-2,3- OH CH₂ dihydrobenzo[b][1,4] dioxin-6-yl

TABLE 3 Representative Compounds of Formula (I) wherein R³ and R⁴ aretaken together to form a ring structure

ID —R³—R⁴— No. R¹ R² together R⁵ R⁶

54 CH₂— H —CH₂—CH₂— H H 2,3-dihydro-benzo OH O— [b][1,4]dioxin-6-yl 56CH₂— H —CH₂—CH₂— H H chroman-6-yl OH O— 58 CH₂— benzyloxy —CH₂—CH₂— H Hbenzothien-2-yl OH O— 59 CH₂— hydroxy —CH₂—CH₂— H H benzothien-2-yl OHO— 60 CH₂— benzyloxy —CH₂—CH₂— H H 2,3-dihydro-benzo OH O—[b][1,4]dioxin-6-yl 61 CH₂— hydroxy —CH₂—CH₂— H H 2,3-dihydro-benzo OHO— [b][1,4]dioxin-6-yl 62 CH₂— hydroxy —CH₂—CH₂— H H 4-ethyl-phenyl OHO— 63 CH₂— hydroxy —CH₂—CH₂— H H 4-ethoxy-phenyl OH O— 65 CH₂— methoxy—CH₂—CH₂— H H 2,3-dihydro-benzo OH O— [b][1,4]dioxin-6-yl 70 CH₂— H—CH₂—CH₂— H H 5-(pyrrolidin-1-yl- OH O— carbonyl)-6,7-dihydrothieno[3,2- c]pyridin-2-yl 75 CH₂— H —CH(CH₂OH)— H H 2,3-dihydro-OH CH₂—O— benzo[b][1,4] dioxin-6-yl 85 CH₂— H —CH(CH₂OH)— H H2,3-dihydro- OH C(CH₃)₂—O— benzo[b][1,4] dioxin-6-yl 88 CH₂— H —C(CH₂OH)H H 2,3-dihydro- OH (CH₃)—CH₂— benzo[b][1,4] O— dioxin-6-yl 89 CH₂— H—CH₂—CH₂— H H 3,4-dihydro-2H- OH O— quinolin-7-yl 93 CH₂— H —CH(CH₂— H H2,3-dihydro- OH CH₂OH)— benzo[b][1,4] CH₂—O— dioxin-6-yl 94 CH₂— H—CH₂—CH₂— H H 1-methyl-3,4- OH O  dihydro-2H- quinolin-7-yl 95 CH₂— H—CH(CH₃)— H H 2,3-dihydro- OH CH₂—O— benzo[b][1,4] dioxin-6-yl 97 CH₂— H—CH₂—CH₂— H H benzo[b][1,4] OH O— oxazin-7-yl-3-one 105 CH₂— methoxy—CH₂—CH₂— H H 3,4-dihydro-2H- OH O— quinolin-7-yl 107 CH₂— methoxy—CH₂—CH₂— H H 2,3- OH O— dihydrobenzo[b] [1,4]oxathiin-6-yl 108 CH₂—methoxy —CH₂—CH₂— H H 1-methyl-3,4- OH O— dihydro-2H- quinolin-7-yl 124CH₂— H —CH₂—CH₂— H H 2,3- OH O— dihydrobenzo[b] [1,4]oxathiin-6-yl 131CH₂— methyl —CH₂—CH₂— H H 2,3- OH O— dihydrobenzo[b] [1,4]oxathiin-6-yl133 CH₂— H —CH₂—CH₂— H H 4-(fluoro-me- OH O— thoxy)-phenyl 134 CH₂— H—CH₂—CH₂— H H 4-ethyl-phenyl OH O— 135 CH₂— methoxy —CH₂—CH₂— H H4-ethyl-phenyl OH O— 142 CH₂— methoxy —CH₂—CH₂— H H 4-(fluoro-me- OH O—thoxy)-phenyl 153 CH₂— H —O—CH₂— H H 2,3-dihydro- OH CH₂— benzo[b][1,4]dioxin-6-yl 160 CH₂— OCD₃ —CH₂—CH₂— H H 2,3-dihydro- OH O— benzo[b][1,4]dioxin-6-yl 161 CH₂— OCD₃ —CH₂—CH₂— D D 2,3-dihydro- OH O— benzo[b][1,4]dioxin-6-yl 163 CH₂— methoxy —CH₂—CH₂— D D 2,3-dihydro- OH O—benzo[b][1,4] dioxin-6-yl 172 CH₂— methoxy —CH₂—CH₂— H H 2,2,3,3-tetra-OH O— deutero-2,3- dihydrobenzo[b] [1,4]dioxin-6-yl 181 CH₂— H —O—CH₂— HH 2,2,3,3-tetra- OH CH₂— deutero-2,3- dihydrobenzo[b] [1,4]dioxin-6-yl

The present invention is further directed to compounds of formula (V-S)

wherein A¹, A² and A³ are as herein defined. The present invention isfurther directed to a process for the preparation of compounds offormula (V-S) as described in more detail herein. The compounds offormula (V-S) are useful as intermediates in the synthesis ofpharmaceutically active compounds, including but not limited to thecompounds of formula (I) of the present invention.

In certain embodiments of the present invention, A¹, A² and A³ are eachan independently selected from the group consisting of C₁₋₄alkyl.

In certain embodiments of the present invention A¹, A² and A³ are eachan independently selected from the group consisting of C₁₋₄alkyl, phenyland 3,5-di(trifluoromethyl)phenyl. In certain embodiments of the presentinvention, A¹, A² and A³ are each an independently selected from thegroup consisting of C₁₋₄alkyl. In certain embodiments of the presentinvention A¹, A² and A³ are each an independently selected from thegroup consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl andbicyclo[2.2.1]heptan-2-yl.

In certain embodiments, the present invention is directed to any one ormore compounds of formula (V-S), wherein

A¹ is methyl, A² is methyl and A³ is t-butyl; or

A¹ is methyl, A² is methyl and A³ is 2,3,3-trimethylbutan-2-yl; or

A¹ is methyl, A² is methyl and A³ is isopropyl; or

A¹ is methyl, A² is methyl and A³ is cyclohexyl; or

A¹ is methyl, A² is methyl and A³ is bicyclo[2.2.1]heptan-2-yl; or

A¹ is methyl, A² is methyl and A³ is phenyl; or

A¹ is methyl, A² is methyl and A³ is 3,5-di(trifluoromethyl)phenyl; or

A¹ is t-butyl, A² is phenyl and A³ is phenyl.

In certain embodiment of the present invention, the compound of formula(V-S) is(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one,wherein A¹ is t-butyl, A² is methyl and A³ is methyl.

Definitions

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine. Preferably, the halogen is selected from the group consisting ofchlorine and fluorine, more preferably fluorine.

As used herein, unless otherwise noted, the term “acyl” shall mean agroup of the formula —C(O)R, wherein R is alkyl, optionally substitutedaryl, and the like. Suitable examples include, but are not limited toacetyl, propanoyl, isopropanoyl, benzoyl, 4-methylbenzoyl,4-methoxybenzoyl, dichloroacetyl, trichloroacetyl, methoxyacetyl,phenoxyacetyl, p-chlorophenoxyacetyl, phenylacetyl, pivaloyl and thelike.

As used herein, the term “C_(X-Y)alkyl” wherein X and Y are integers,whether used alone or as part of a substituent group, include straightand branched chains containing between X and Y carbon atoms. Forexample, C₁₋₄alkyl radicals include straight and branched chains ofbetween 1 and 4 carbon atoms, including methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

As used herein, unless otherwise noted, the terms “fluorinatedC_(X-Y)alkyl” and “fluoro substituted C_(X-Y)alkyl” shall mean anyC_(X-Y)alkyl group as defined above substituted with at least onefluorine atom, preferably one to three fluorine atoms. In an example,“fluorinated C₁₋₄alkyl” include, but are not limited, to —CH₂F, —CF₂H,—CF₃, —CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “hydroxy substitutedC_(X-Y)alkyl” shall mean any C_(X-Y)alkyl group as defined abovesubstituted with at least one hydroxy, preferably one to two hydroxygroups, wherein the hydroxy group(s) may be bound to any carbon atom ofthe C_(X-Y)alkyl, preferably, the hydroxy group(s) are bound to theterminal carbon atom. In an example, “hydroxy substituted C₁₋₄alkyl”include, but are not limited, to —CH₂OH, —CH₂—CH₂OH, —CH(OH)—CH₃,—CH(OH)—CH₂OH, —CH₂—CH₂—CH₂OH, —CH(OH)—CH₂—CH₃, —CH(OH)(CH₃)₂, and thelike.

As used herein, unless otherwise noted, “C₁₋₄alkoxy” shall denote anoxygen ether radical of the above described straight or branched chainalkyl groups containing one to four carbon atoms. For example, methoxy,ethoxy, n-propoxy, isopropoxy, sec-butoxy, t-butoxy, and the like.

As used herein, unless otherwise noted, the terms “fluorinatedC_(X-Y)alkoxy” and “fluoro substituted C_(X-Y)alkoxy”, shall mean anyC_(X-Y)alkoxy group as defined above substituted with at least onefluorine atom, preferably one to three fluorine atoms. In an example,“fluorinated C₁₋₄alkoxy” include, but are not limited, —OCH₂F, —OCF₂H,—OCF₃, —OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “cyano substitutedC_(X-Y)alkoxy” shall mean any C_(X-Y)alkoxy group as defined abovesubstituted with one cyano group, wherein the cyano group may be boundto any carbon atom of the C_(X-Y)alkoxy, preferably, the cyano group arebound to the terminal carbon atom. In an example, “cyano substitutedC₁₋₄alkoxy” include, but are not limited, to —O—CH₂CN, —O—CH₂—CH₂CN,—O—CH(CN)—CH₃, —O—CH(CN)—CH₂OH, —O—CH₂—CH₂—CH₂CN, —O—CH(CN)—CH₂—CH₃,—O—CH(CN)(CH₃)₂, and the like.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkyl”,wherein X and Y are integers, shall mean any stable X- to Y-memberedmonocyclic, bicyclic, polycyclic or bridges saturated ring system,preferably a monocyclic or bicyclic saturated ring system. For example,the term “C₃₋₁₂cycloalkyl” includes, but is not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, and the like.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkenyl”,wherein X and Y are integers, shall mean any stable X- to Y-memberedmonocyclic, bicyclic, polycyclic or bridged, preferably a monocyclic orbicyclic, ring system containing at least one, preferably one to three,unsaturated double bonds. For example, the term “C₆₋₁₀cycloalkenyl”includes, but is not limited to cyclohexenyl, bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl, and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or an eight to ten membered saturated, partially unsaturated,partially aromatic or benzo-fused bicyclic ring system containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to four additional heteroatoms independentlyselected from the group consisting of O, N and S. The heterocycloalkylgroup may be attached at any heteroatom or carbon atom of the ring suchthat the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

When a particular group is “substituted” (e.g. alkyl, alkoxy,cycloalkyl, etc.), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

As used herein, unless otherwise noted, the term “isotopologues” shallmean molecules that differ only in their isotopic composition. Moreparticularly, an isotopologue of a molecule differs from the parentmolecule in that it contains at least one atom which is an isotope (i.e.has a different number of neutrons from its parent atom).

For example, isotopologues of water include, but are not limited to,“light water” (HOH or H₂O), “semi-heavy water” with the deuteriumisotope in equal proportion to protium (HDO or ¹H²HO), “heavy water”with two deuterium isotopes of hydrogen per molecule (D₂O or ²H₂O),“super-heavy water” or tritiated water (T₂O or ³H₂O), where the hydrogenatoms are replaced with tritium (³H) isotopes, two heavy-oxygen waterisotopologues (H₂ ¹⁸O and H₂ ¹⁷O) and isotopologues where the hydrogenand oxygen atoms may each independently be replaced by isotopes, forexample the doubly labeled water isotopologue D₂ ¹⁸O.

It is intended that within the scope of the present invention, any oneor more element(s), in particular when mentioned in relation to acompound of formula (I), shall comprise all isotopes and isotopicmixtures of said element(s), either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, a reference to hydrogen includes within its scope ¹H,²H (D), and ³H (T). Similarly, references to carbon and oxygen includewithin their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. Theisotopes may be radioactive or non-radioactive. Radiolabelled compoundsof formula (I) may comprise one or more radioactive isotope(s) selectedfrom the group of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Brand ⁸²Br. Preferably, the radioactive isotope is selected from the groupof ³H, ¹¹C and ¹⁸F.

In certain embodiments, the present invention is directed to compoundsof formula (I) wherein R² is OCD₃. In certain embodiments, the presentinvention is directed to compounds of formula (I) wherein the R⁵ and R⁶groups are the same and are both deuterium (D). In certain embodiments,the present invention is directed to compounds of formula (I) wherein

is 2,2,3,3-tetradeutero-dihydrobenzo[b][1,4]dioxin-6-yl.

In certain embodiments, the present invention is directed to compoundsof formula (I) wherein any C₁₋₄alkyl or C₁₋₄alkoxy substituent isdeuterated (i.e. wherein one or more hydrogen atoms on the substituentgroup are replaced with a deuterium atom (D), preferably one to threehydrogen atoms are each replaced with a deuterium atom), for example—CD₃, —CH₂CD₃, —OCD₃, and the like.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

One skilled in the art will recognize that when R² and R³ or R³ and R⁴are taken together with the carbon atoms to which they are bound to form2,3-dihydrofuranyl or 3,4-dihydro-2H-pyranyl, said 2,3-dihydrofuranyl or3,4-dihydro-2H-pyranyl ring structure is one ring of a bicyclic ringstructure. More particularly, when R² and R³ or R³ and R⁴ are takentogether with the phenyl ring to which they are bound (through thecarbon atoms to which they are bound), the resulting structure is apartially unsaturated, benzo-fused bicyclic ring structure. Thus, forexample, when R² and R³ are taken together with the carbon atoms towhich they are bound to form 2,3-dihydrofuranyl, a group of thefollowing structure, with numbering order as indicated

then the resulting bicyclic structure (where R² and R³ are takentogether with the phenyl to which they are bound, through the carbonatoms to which they are bound) is 2,3-dihydrobenzofuranyl, a group ofthe following structure, with numbering order as indicated:

One skilled in the art will further recognize that when R² and R³ or R³and R⁴ are taken together with the phenyl ring to which they are bound(through the carbon atoms to which they are bound) to form thecorresponding benzo-fused bicyclic ring structure, said benzo-fused ringstructure may exist as either of two orientations.

For example, when R² and R³ are taken together with the phenyl ring towhich they are bound (through the carbon atoms to which they are bound)to form the corresponding 2,3-dihydrobenzofuranyl, then the2,3-dihydrobenzofuranyl may be incorporated into the compound of formula(I) in either of two orientations, more particularly as thecorresponding structure (R1)

or the corresponding structure (R2)

One skilled in the art will further recognize that the orientation ofthe compound of formula (I) can be identified by its drawn structure(for example as shown at the head of the Examples which followhereinafter), or by the chemical name which identifies the bindingorientation of the 2,3-dihydro-benzofuranyl or isochromanyl ringstructure within the complete compound of formula (I).

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   18-Crown-6=1,4,7,10,13,16-hexaoxacyclooctadecane-   AcCl=Acyl chloride-   AcOH or HOAc=Acetic acid-   ARB=Angiotensin receptor blockers-   CAN=Acetonitrile-   AMG=Alpha-Methyl Glucopyranoside-   aq.=aqueous-   BAlB=Bis-acetoxyiodobenzene-   BF₃.Et₂O=Boron trifluoride diethyl etherate-   BnBr=Benzylbromide-   Boc=tert-Butoxycarbonyl-   Boc₂O=Boc anhydride (Di-tert-butyl dicarbonate)-   Bu₄NCl=Tetrabutylammonium chloride-   n-Bu₄NF Tetra-n-butylammonium fluoride-   n-BuLi=n-Butyl lithium-   sec-BuLi=sec-Butyl lithium-   t-BuLi=tert-Butyl lithium-   n-Bu₄NI=Tetra-n-butylammonium iodide-   t-BuOH=tert-Butanol-   t-BuONa or NaOt-Bu=Sodium tert-butoxide-   conc.=concentrated-   [CpRu(CH₃CN)₃]PF₆=Pentamethylcyclopentadienyltris    (acetonitrile)ruthenium(II) hexafluorophosphate-   DABCO=1,4-Diazabicyclo[2.2.2]octane-   DAST=Diethylaminosulfur trifluoride-   DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCC=N,N′-Dicyclohexylcarbodiimide-   DCM=Dichloromethane-   Dess-Martin Reagent or Dess-Martin    Periodinane=1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one-   DEXOX-FLKUOR®=Bis(2-methoxyethyl)aminosulfur trifluoride-   DIBAL or DIBAL-H=Diisobutylaluminium hydride-   DIPEA or DIEA=Diisopropylethylamine-   DMF=N,N-Dimethylformamide-   DMPU-HF=1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone—Hydrogen    fluoride Complex-   DMSO=Dimethylsulfoxide-   EDCI=1-Ethyl-3-(3-dimetylaminopropyl)carbodiimide-   Et₂O=Diethyl Ether-   Et₃N or TEA=Triethylamine-   Et₃NHPF₆=Triethylammonium hexafluorophosphate-   Et₃SiD=Mono-deuterated Triethylsilane-   Et₃SiH=Triethylsilane-   EtOAc or EA=Ethyl acetate-   EtOH=Ethanol-   GCMS=Gas chromatography-mass spectrometry-   HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N″,N″-Tetramethyl Uronium    Hexafluorophosphate-   HDL=High density lipoprotein-   HEPES=4-(2-Hydroxyethyl)-1-Piperizine Ethane Sulfonic Acid-   HOBT=1-Hydroxybenzotriazole-   HMPA=Hexamethylphosphoramide-   HPLC=High Pressure Liquid Chromatography-   HRuCl(PPh₃)₃=Chlorohydridotris(triphenylphosphine)ruthenium (II)    complex-   IDDM=Insulin-dependent Diabetes Mellitus-   IFG=Impaired fasting glucose-   IGT=Impaired glucose tolerance-   [Ir(Ph2MeP)2(cod)]*PF⁶⁻=(1,5-Cyclooctadiene)(pyridine)    (tricyclohexylphosphine)-iridium(I) hexafluorophosphate-   IRS=Insulin resistance syndrome-   Jones reagent=solution of chromium trioxide or sodium dichromate in    diluted sulfuric acid-   LAH=Lithium aluminum hydride-   LC-MS or LCMS=Liquid chromatography-mass spectrometry-   Me=Methyl (i.e. —CH₃)-   MeCN=Acetonitrile-   MeI=Methyl iodide-   MeOH=Methanol-   MeSO₃H=Methanesulfonic acid-   Mesyl or Ms=Methylsulfonyl-   MOM=Methoxy methyl-   MsCl=Mesyl chloride-   MTBE=Methyl t-butyl ether-   NAFLD=Non-alcoholic fatty liver disease-   NASH=Non-alcoholic steatohepatitis,-   NaOMe=Sodium methoxide-   NaOEt=Sodium Ethoxide-   NBS=N-Bromosuccinimide-   NIS=N-Iodosuccinimide-   NIDDM=Non-insulin-dependent Diabetes Mellitus-   NMO=N-Methylmorpholine-N-oxide-   NMR=Nuclear magnetic resonance-   OMe=Methoxy-   OTf=Trifluoromethanesulfonate (triflate)-   PCC=Pyridinium chlorochromate-   Pd₂Cl₂(PhCN)₂=Bis(benzonitrile)palladium chloride-   Pd(OAc)₂=Palladium acetate-   Pd(PPh₃)₄=Tetrakistriphenylphosphine palladium (0)-   PE=Petroleum ether-   PHENOFLUOR™=1,3-Bis(2,6-diisopropylphenyl)-2,2-difluoro-2,3-dihydro-1H-imidazole-   PhI(OAc)₂=(Diacetoxyiodo)benzene-   (Ph₃P)₂CpRuCl=Bis(triphenylphosphine)cyclopentadienyl ruthium    chloride-   (PPh₃)₃RhCl=Chloridotris(triphenylphosposphane)rhodium(I)    (Wilkinson's catalyst)-   i-PrOH or IPA=Isopropanol-   iPrMg.LiCl=Isopropyl magnesium chloride/Lithium chloride complex-   PyFluor=2-Pyridinesulfonyl Fluoride-   RAS=Renin-angiotensin system-   Rh₂-(S-DOSP)₄=Tetrakis[(R)-(+)-N-(p-dodecylphenylsulfonyl)prolinato]dirhodium(II)-   SELECTFLUO®=1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane    bis(tetrafluoroborate-   SGLT=Sodium glucose transport-   SGLT1=Sodium glucose transport-1-   SGLT2=Sodium glucose transport-2-   TBAI=Tetrabutylammonium iodide-   TBDMS=tert-Butyldimethylsilyl-   TBDMSCl=tert-Butyldimethylsilyl chloride-   TBDMSOTf or tert-BuMe₂SiOTf=tert-Butyldimethylsilyl    trifluoromethanesulfonate-   TBDPS=tert-Butyl-diphenyl-silyl-   TBDPSCl=tert-Butyl-diphenyl-silyl chloride-   TEA=Triethylamine-   TEMPO=(CH₃)₄-piperidoxyl (also known as    (2,2,6,6-tetramethylpiperidin-1-yl)oxidany))-   TFA=Trifluoroacetic Acid-   THF=Tetrahydrofuran-   THP=Tetrahydropyran-   TLC=Thin Layer Chromatography-   TMS=Trimethylsilyl-   TMEDA=Tetramethylethylenediamine-   TMSCl=Trimethylsilyl chloride-   Tosyl or Ts=p-Toluenesulfonyl-   TrCl=Triphenylmethyl chloride or trityl chloride-   TsCl=Tosyl chloride-   TsOH or p-TsOH=p-Toluenesulfonic acid-   Tris HCl or Tris-Cl or Tris=Tris[hydroxymethyl]aminomethyl    hydrochloride buffer-   XTALFLUOR-E®=(Diethylamino)difluorosulfonium tetrafluoroborate-   XTALFLUOR-M®=(Difluoro(morpholino)sulfonium tetrafluoroborate

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, the compound offormula (I) is present in an isolated form.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I) is present as asubstantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I) shall mean that mole percent of the corresponding saltform(s) in the isolated base of formula (I) is less than about 5 molepercent, preferably less than about 2 mole percent, more preferably,less than about 0.5 mole percent, most preferably less than about 0.1mole percent. In an embodiment of the present invention, the compound offormula (I) is present in a form which is substantially free ofcorresponding salt form(s).

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, slow the progression of the disease or disorder, oreliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

One skilled in the art will further recognize that the reaction orprocess step(s) as herein described are allowed to proceed for asufficient period of time until the reaction is complete, as determinedby any method known to one skilled in the art, for example,chromatography (e.g. HPLC). In this context a “completed reaction orprocess step” shall mean that the reaction mixture contains asignificantly diminished amount of the starting material(s)/reagent(s)and a significantly reduced amount of the desired product(s), ascompared to the amounts of each present at the beginning of thereaction.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follow herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, andthe like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂=CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to an oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:

ee=([α-obs]/[α-max])×100.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) of the present invention may be synthesizedaccording to the general synthesis schemes described below. Thepreparation of the various starting materials used in the synthesisschemes which follow hereinafter is well within the skill of personsversed in the art.

Compounds of formula (I) wherein R¹ is hydroxy-methyl- (i.e. —CH₂OH) maybe prepared as described in Scheme 1, below.

Accordingly, a suitably substituted compound of formula (V) wherein PG¹,PG² and PG³ are each an independently selected oxygen protecting groupsuch as benzyl, trimethylsilyl (TMS), t-butyl-dimethyl-silyl (TBDMS),t-butyl-diphenyl-silyl (TBDPS), and the like, is reacted with a suitablysubstituted and optionally protected compound of formula (VI), whereinLG¹ is a suitably selected leaving group such as Br, Cl, I, mesylate,tosylate, trifluoromethanesulfonyl, and the like;

in the presence of a suitably selected organolithium or Grignard reagentsuch as n-BuLi, s-BuLi, i-PrMgCl.LiCl, and the like; in a suitablyselected organic solvent such as THF, TMEDA(tetramethylethylenediamine), HMPA (hexamethylphosphoramide), and thelike; at a temperature less than about room temperature, preferably atabout −78° C.; to yield the corresponding compound of formula (VII).

The compound of formula (VII) is reacted with a suitably selectedreducing agent such as a mixture of Et₃SiH and BF₃.Et₂O, Et₃SiH and TFA,and the like; in a suitably selected organic solvent such as DCM, amixture of DCM and acetonitrile, CHCl₃, and the like; to yield thecorresponding compound of formula (VIII).

The compound of formula (VIII) is de-protected (in one or more steps),according to known methods, to remove the PG¹, PG² and PG³ groups, andif present, any protecting groups introduced through the compound offormula (VI); to yield the corresponding compound of formula (Ia).

For example, wherein one or more of PG¹, PG² and/or PG³ are benzyl, saidgroup(s) may be removed by reacting with a BCl₃ in the presence of1,2,3,4,5-pentamethylbenzene, in an organic solvent such as DCM, atabout −78° C.; or by reacting with hydrogen in the presence of Pd/C, inan organic solvent such as MeOH; or reacting with hydrogen, in thepresence of Pd(OH)₂/C, in a mixture of organic solvents such as ethylacetate and methanol. In another example, wherein one or more of PG¹,PG² and/or PG³ are a suitably selected silyl group such astrimethylsilyl (TMS), t-butyl-dimethyl-silyl (TBDMS),t-butyl-diphenyl-silyl (TBDPS), and the like, said group(s) may beremoved by reacting with a suitably selected reagent or mixture ofreagents such as n-Bu₄NF, HF-pyridine, KF, Bu₄NCl/KF.H₂O, and the like;wherein the reaction with HF, NH₄F—HF, Bu₄NCl/KF.H₂O, and the like is ina suitably selected organic solvent such as THF, 18-crown-6, methanol,acetonitrile, cyclohexane, and the like.

Compounds of formula (I) wherein R¹ is hydroxy-methyl- (i.e. —CH₂—OH)and wherein R⁵ and R⁶ are each hydrogen may alternatively be prepared asdescribed in Scheme 2, below.

Accordingly, a suitably substituted compound of formula (V), for examplea compound of formula (V) wherein PG¹, PG² an PG³ are each benzyl, isreacted with a suitably substituted compound of formula (IX), whereinLG² is a suitably selected leaving group such as Br, I, mesylate,tosylate, trifluoromethanesulfonyl, and the like, a known compound orcompound prepared by known methods,

in the presence of a suitably selected organolithium or Grignard reagentsuch as n-BuLi, s-BuLi, i-PrMgCl.LiCl, and the like; in a suitablyselected organic solvent such as THF, diethyl ether, HMPA, and the like;at a temperature less than about room temperature, preferably at about−78° C.; to yield the corresponding compound of formula (X).

The compound of formula (X) is reacted with a suitably selected acidsuch as HCl, diluted H₂SO₄, TFA, and the like; in a suitably selectedorganic solvent such as THF, diethyl ether, MeOH, and the like; to yieldthe corresponding compound of formula (XI).

The compound of formula (XI) is reacted with a suitably substituted, andoptionally protected, compound of formula (XII), wherein LG³ is asuitably selected leaving group such as Br, I, mesylate, tosylate,trifluoromethanesulfonyl, and the like, a known compound or compoundprepared by known methods; in the presence of a suitably selectedorganolithium reagent such as n-BuLi, s-BuLi, t-BuLi, and the like; in asuitably selected organic solvent such as THF, diethyl ether,2-methyltetrahydrofuran, and the like; at a temperature less than aboutroom temperature, preferably at about −78° C.; to yield thecorresponding compound of formula (XIII).

The compound of formula (XIII) is reacted with a suitably selectedreducing agent such as a mixture of Et₃SiH and BF₃.Et₂O, Et₃SiH and TFA,and the like; in a suitably selected organic solvent such as DCM, amixture of DCM and acetonitrile, CHCl₃, THF, and the like; to yield thecorresponding compound of formula (XIV).

The compound of formula (XIV) is de-protected according to knownmethods, or according to methods as described herein; to yield thecorresponding compound of formula (Ib).

Compounds of formula (I) wherein R¹ is selected from the groupconsisting of —C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl (including—CH(OH)CH₃, —C(OH)(CH₃)₂), —CH₂—F, —CH₂—CN, —CH₂—NH₂, —CH₂—O-(methyl orethyl), —C₃₋₆cycloalkyl, —C₃₋₆cycloalkyl-OH, —C(O)OH and—C(O)O—(C₁₋₄alkyl), may be prepared from the corresponding compound offormula (XV) or compound of formula (XVI), which compounds may beprepared as described in Scheme 3 below.

Accordingly, a suitably substituted compound (VIII) is selectivelydeprotected according to known methods, to yield the correspondingcompound of formula (XV). For example, wherein PG¹ benzyl, the compoundof formula (VIII) is selectively deprotected under hydrogen atmospherein the presence of catalyst such as 5% Pd on carbon, 10% Pd/C, 20% ofPd(OH)₂, and the like, to yield the corresponding compound of formula(XV).

The compound of formula (XV) is then optionally reacted with a suitablyselected oxidizing agent such as Dess-Martin reagent, DMSO/oxalylchloride, PCC, and the like; in a suitably selected organic solvent suchas 1,2-dichloroethane, chloroform, dichloromethyl (DCM), and the like;to yield the corresponding compound of formula (XVI) (wherein thehydroxymethyl (i.e. —CH₂OH) group is converted to the correspondingaldehyde (i.e —CH═O) group.

Compounds of formula (I) wherein R¹ is hydroxy substituted C₁₋₄alkyl maybe prepared by reacting a suitably substituted compound of formula (XVI)with a suitably selected C₁₋₄alkylmagnesium bromide or C₁₋₄alkyllithium,a known compound or compound prepared by known methods, in a suitablyselected organic solvent such as THF, 2-methyl tetrahydrofuran(2-Me-THF), diethyl ether, and the like; to yield the correspondingcompound wherein the aldehyde group is converted to the correspondinghydroxy-substituted C₁₋₄alkyl group; and then de-protecting saidcompound as described herein, to remove the PG² and PG³ groups; to yieldthe compound of formula (I) wherein R¹ is hydroxy substituted C₁₋₄alkyl.

One skilled in the art will recognize that compounds of formula (I)wherein R¹ is hydroxy substituted C₃₋₆cycloalkyl, may be similarlyprepared by substituting a suitably selected C₃₋₆cycloalkyl magnesiumbromide for the C₁₋₄alkylmagnesium bromide, and reacting as described inthe paragraph above.

Compounds of formula (I) wherein R¹ is C₁₋₄alkyl may be similarlyprepared by reacting a suitably substituted compound of formula (XVI)with a suitably selected C₁₋₄alkylmagnesium bromide or C₁₋₄alkyllithium,a known compound or compound prepared by known methods, in a suitablyselected organic solvent such as THF, 2-methyl tetrahydrofuran(2-Me-THF), diethyl ether, and the like; to yield the correspondingcompound wherein the aldehyde group is converted to the correspondinghydroxy-substituted C₁₋₄alkyl group; reacting said hydroxy-substitutedC₁₋₄alkyl substituted compound with for example, BF₃.Et₂O and Et₃SiH ina solvent such as DCM; to yield the corresponding compound wherein thehydroxy-substituted C₁₋₄alkyl group is converted to the correspondingC₁₋₄alkyl; and then de-protecting said C₁₋₄alkyl substituted compound asdescribed herein, to remove the PG² and PG³ groups; to yield thecompound of formula (I) wherein R¹ is C₁₋₄alkyl.

One skilled in the art will recognize that compounds of formula (I)wherein R¹ is C₃₋₆cycloalkyl, may be similarly prepared by substitutinga suitably selected C₃₋₆cycloalkyl magnesium bromide for theC₁₋₄alkylmagnesium bromide, and reacting as described in the paragraphabove.

Compounds of formula (I) wherein R¹ is —CH₂F may be prepared by reactinga suitably substituted compound of formula (XV) with a suitably selectedfluorinating agent such as DAST, DEXOX-FLUOR®, and the like, in asuitably selected organic solvent such as DCM, chloroform, and the like;to yield the corresponding compound wherein the R¹ group (i.e the —CH₂OHsubstituent group) is mono-fluorinated (i.e. converted to thecorresponding —CH₂F group); and then de-protecting said compound toremove the PG² and PG³; to yield the corresponding compound of formula(I), where R¹ is CH₂F.

Compounds of formula (I) wherein R¹ is —CH₂—CN may be prepared byreacting a suitably substituted compound of formula (XV) with a suitablyselected sulfonating agent such as MsCl, TsCl, and the like; in thepresence of a suitably selected base such as Et₃N, DIPEA, pyridine, andthe like, to yield the corresponding compound wherein R¹ group (i.e the—CH₂OH substituent group) is converted to the corresponding mesylate ortosylate; said mesylate or tosylate substituted compound is then furtherreacted with for example, KCN, NaCN, and the like; in a suitablyselected organic solvent such as DMF, DMSO, and the like; to thecorresponding compound wherein the mesylate or tosylate group isconverted to cyanomethyl (i.e. —CH₂CN); which compound is thende-protected as described herein, to remove the PG² and PG³; to yieldthe corresponding compound of formula (I), where R¹ is CH₂CN.

Alternatively, the mesylate or tosylate substituted compound may bereacted with for example, NaN₃ in DMF or DMSO; to yield thecorresponding compound wherein the mesylate or tosylate group isconverted to azidomethyl—(i.e. —CH₂N₃); which compound is then reducedand de-protected (to remove the PG² and PG³ groups) in one pot byreacting with H₂ gas in the presence of catalyst such as 5% Pd/C, 10%Pd/C, 20% Pd(OH)₂, and the like; to yield the corresponding compound offormula (I) where R¹ is CH₂NH₂.

Compounds of formula (I) wherein R¹ is —CH₂—OCH₃ or —CH₂—OCH₂CH₃ may beprepared by reacting a suitably substituted compound of formula (XV)with a suitably selected sulfonating agent such as MsCl, TsCl, and thelike; in the presence of a suitably selected base such as Et₃N, DIPEA,pyridine, and the like, to yield the corresponding compound wherein R¹group (i.e the —CH₂OH substituent group) is converted to thecorresponding mesylate or tosylate; said mesylate or tosylatesubstituted compound is then further reacted with NaOCH₃ or NaOCH₂CH₃,in a suitably selected organic solvent such as THF, DMF, and the like;to yield the corresponding compound wherein the mesylate or tosylate isconverted to the corresponding —CH₂—OCH₃ or —CH₂—OCH₂CH₃ group,respectively; which compound is then de-protected as described herein,to remove the PG² and PG³; to yield the corresponding compound offormula (I), where R¹ is —CH₂—OCH₃ or —CH₂—OCH₂CH₃ group.

Compounds of formula (I) wherein R¹ is —C(O)OH may be prepared byreacting a suitably substituted compound of formula (XV) with a suitablyselected oxidizing agent such as CrO₃/H₂SO₄, KMnO₄, PhI(OAc)₂[(diacetoxyiodo)benzene or bis-acetoxyiodobenzene(BAlB)]/(CH₃)₄-piperidoxyl (TEMPO), and the like, in a suitably selectedsolvent such as acetone, a mixture of ACN/water, and the like; to yieldthe corresponding compound wherein the R¹ group (i.e the —CH₂OHsubstituent group) is converted to the corresponding carboxylic acidgroup (i.e —C(O)OH). Said carboxylic acid substituted compound is thende-protected as described herein, to remove the PG² and PG³; to yieldthe corresponding compound of formula (I), where R¹ is —C(O)OH.

Compounds of formula (I) wherein R¹ is —C(O)O—(C₁₋₄alkyl) may beprepared by reacting a suitably substituted compound of formula (XV)with a suitably selected oxidizing agent such as CrO₃/H₂SO₄, KMnO₄,PhI(OAc)₂ [(diacetoxyiodo)benzene or bis-acetoxyiodobenzene(BAlB)]/(CH₃)₄-piperidoxyl (TEMPO), and the like, in a suitably selectedsolvent such as acetone, a mixture of ACN/water, and the like; to yieldthe corresponding compound wherein the R¹ group (i.e the —CH₂OHsubstituent group) is converted to the corresponding carboxylic acidgroup (i.e —C(O)OH). Said carboxylic acid substituted compound is thenreacted with a suitably selected C₁₋₄alkyl alcohol, in the presence of asuitably selected coupling agent such as DCC, EDCl/HOBt, and the like;in a suitably selected organic solvent such as DCM, THF, DMF, and thelike; to yield the corresponding compound wherein the carboxylic acidgroup (i.e. —C(O)OH) is functionalized to the corresponding C₁₋₄alkylester group (i.e. —C(O)O—(C₁₋₄alkyl) group); and then said C₁₋₄alkylester substituted compound is de-protected as described herein, toremove the PG² and PG³; to yield the corresponding compound of formula(I), where R¹ is —C(O)O—(C₁₋₄alkyl).

One skilled in the art will recognize that compounds of formula (VI)

are known compounds or compounds which may be prepared by known methodsor compounds which may be prepared according to the methods as describedin the Schemes and Examples herein.

Compounds of formula (I) wherein R², R³ and R⁴ are each independently asubstituent group may be prepared as described in Scheme 4, below.

Accordingly, a suitably substituted compound of formula (XVII), a knowncompound or compound prepared by known methods, is reacted with forexample, a suitably selected coupling reagent such as HATU, EDCl/HOBt,and the like; in the presence of a suitably selected base such as Et₃N,DIPEA, and the like; in a suitably selected organic solvent such as DCM,DMF, and the like;

to yield the corresponding compound of formula (XVIII) wherein thecarboxylic acid substituent group on the compound of formula (XVII) isconverted to a Weinreb amide.

The compound of formula (XVIII) is pre-treated (and admixed with) asuitably selected base such as n-BuLi, t-BuLi, sec-BuLi and the like; ina suitably selected organic solvent such as THF, diethyl ether, and thelike; at a temperature in the range of from about −78° C. to about 20°C., preferably at a temperature of about −78° C.; and then immediatelyreacted with a suitably substituted compound of formula (XII), whereinLG³ is a suitably selected leaving group such as Br, I, and the like; aknown compound or compound prepared by known methods, to yield thecorresponding compound of formula (XIX).

The compound of formula (XIX) is reacted with a suitably selectedreducing agent such as triethylsilane, LAH, and the like; in thepresence of suitably selected Lewis acid such as BF₃.Et₂O, TFA, AlCl₃,and the like; in a suitably selected organic solvent such as DCM,diethyl ether, and the like; to yield the corresponding compound offormula compound formula (VI), wherein R⁵ and R⁶ are each hydrogen.

Alternatively, the compound of formula (XIX) is reacted with a suitablyselected reducing agent such as deuterium-substituted triethylsilane(triethylsilane-d₄), deuterium-substituted LAH, and the like; in thepresence of suitably selected Lewis acid such as BF₃.Et₂O, TFA, AlCl₃,and the like; in a suitably selected organic solvent such as DCM,diethyl ether, and the like; to yield the corresponding compound offormula (VI), wherein R⁵ and R⁶ are each deuterium.

Compounds of formula (I) wherein R² and R³ or R³ and R⁴ are takentogether with the carbon atoms to which they are bound to form a ringstructure as herein defined may be prepared as described in Scheme 5,below.

Accordingly, a suitably substituted compound of formula (XX), a knowncompound or compound prepared by known methods, is reacted with a firstsuitably selected brominating reagent such as Br₂, NBS, and the like; ina suitably selected organic solvent such as DCM, THF, CH₃CN, and thelike; to yield the corresponding compound of formula (XXI) wherein LG¹is bromine.

The compound of formula (XXI) is reacted with a second suitably selectediodinating reagent such as I₂, NIS, and the like; in a suitably selectedorganic solvent such as DCM, THF, CH₃CN and the like; to yield thecorresponding compound of formula (XXII) wherein LG¹ is bromine andwherein LG⁴ is iodine.

The compound of formula (XXII) is reacted with a suitably selectedorganolithium or Grignard reagent such as n-BuLi, s-BuLi, i-PrMgCl.LiCl,and the like; and the resulting intermediate (which is not isolated) isthen immediately reacted with DMF; to yield the compound of formula(XXIII).

The compound of formula (XII) wherein LG³ is a suitably selected leavinggroup such as Br, Cl, I, and the like; a known compound or compoundprepared by known methods; in a suitably selected organic solvent suchas THF, diethyl ether, and the like; at a temperature in the range offrom about −78° C. to about 20° C., preferably at about −78° C.; ispre-treated (and admixed with) a suitably selected base such as n-BuLi,t-BuLi, sec-BuLi and the like; and then immediately reacted with asuitably substituted compound of formula (XXIII), to yield thecorresponding compound of formula of (XXIV).

The compound of formula (XXIV) is reacted with a suitably selectedreducing agent such as triethylsilane, LAH, and the like; in thepresence of suitably selected Lewis acid such as BF₃.Et₂O, TFA, AlC₃,and the like; in a suitably selected organic solvent such as DCM,diethyl ether, and the like; to yield compound formula (VI), wherein R⁵and R⁶ are each H.

Alternatively, the compound of formula (XXIV) is reacted with a suitablyselected oxidizing reagent such as PCC, MnO₂, Dess-Martin reagent, andthe like; in a suitably selected organic solvent such as DCM,1,2-dicholorethane, DMSO and the like; to yield the compound of formula(XXV).

The compound of formula (XXV) is reacted with a suitably selectedreducing agent such as deuterium-substituted triethylsilane(triethylsilane-d4), deuterium-substituted LAH, and the like; in thepresence of suitably selected Lewis acid such as BF₃.Et₂O, AlCl₃, andthe like; in a suitably selected organic solvent such as DCM, diethylether, and the like; to yield compound formula (VI), wherein R⁵ and R⁶are each deuterium.

In certain embodiments, the present invention is directed to compoundsof formula (V-S), and a method for the preparation of the compounds offormula (V-S).

The compound of formula (V-S), for example, compounds of formula (V-S)wherein A¹ is t-butyl, A² is methyl and A³ is methyl, may be prepared asdescribed in Scheme A, below.

Accordingly,(2S,3R,4S,5R,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,a known compound or compound prepared by known methods, is reacted witha suitably selected acylating agent such as an acyl chloride, acylanhydride, and the like, including, but not limited to acetyl chloride,acetic anhydride, propanoyl chloride, isopropanoyl chloride, pivaloylchloride, trichloroacetyl chloride, benzoyl chloride, 4-methoxy benzoylchloride, benzoyl anhydride, 4-methyl-benzoyl chloride, and the like,wherein the acylating agent is preferably present in an amount in therange of from about 1 to about 3.9 molar equivalents (relative to themoles of the starting material), more preferably about 3 to about 3.5molar equivalents, more preferably, between about 3 and about 3.25 molarequivalents, for example, about 3.1 molar equivalents;

in the presence of an inorganic or organic base, preferably a base whichis soluble in the reaction solvent, more preferably an organic base suchas pyridine, DIPEA, Et₃N, and the like; wherein the inorganic or organicbase is preferably present in an amount in the range of from about 1 toabout 20 molar equivalents, preferably in an amount in the range of fromabout 2 to about 10 molar equivalents, more preferably in an amount inthe range of from about 2 to about 6 molar equivalents, more preferablyin an amount in the range of from about 3 to about 4 molar equivalents,for example, about 3.1 molar equivalents;

neat, when in the presence of an organic base or when in the presence ofan inorganic base, in a suitably selected organic solvent such as DCM,1,2-dichloroethane, chlorobenzene, fluorobenzene, THF, 2-methyl-THF,toluene, di-n-butyl ether, ethyl acetate, acetone, and the like; at atemperature in the range of from about −50° C. to about roomtemperature, preferably at about −35° C. to about 20° C. (preferably ata temperature in the range of from about −35° C. to about 0° C.); toyield the corresponding compound of formula (A-1), wherein W is thecorresponding acyl group, preferably —C(O)-methyl, —C(O)— ethyl,—C(O)-benzyl, more preferably —C(O)-benzyl (benzoyl).

Preferably, the acyl chloride is added a mixture comprising the(2S,3R,4S,5R,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-trioland the base. Preferably, the acyl chloride is added to the mixture at arate which maintains the internal temperature of the reaction mixturebelow 0° C.

The compound of (A-1) is reacted with a suitably selected fluorinatingagent such as DAST, DEXOX-FLUOR® (Bis(2-methoxyethyl)aminosulfurtrifluoride available from Sigma-Aldrich), SELECTFLUOR®(1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) available from Sigma-Aldrich), XTALFLUOR-E®((Diethylamino)difluorosulfonium tetrafluoroborate available fromSigma-Aldrich), XTALFLUOR-M® ((Difluoro(morpholino)sulfoniumtetrafluoroborate available from Sigma-Aldrich), PyFluor(2-Pyridinesulfonyl Fluoride available from Sigma-Aldrich),4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, AlkylFluor (availablefrom Sigma-Aldrich), N-fluorobenzenesulfonimide, DMPU-HF Complex (HF 65%w/w), 1-fluoropyridinium triflate, 1-fluoro-2,4,6-trimethylpyridiniumtetrafluoroborate, 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octanebis(tetrafluoroborate) on aluminum oxide,fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, hydrogenfluoride pyridine (pyridine ˜30%, hydrogen fluoride ˜70%), PHENOFLUOR™solution (0.1 M in toluene), and the like, preferably DAST; wherein thefluorinating agent is preferably present in an amount in the range offrom about 2 to about 10 molar equivalents, (relative to the molaramount of(2S,3R,4S,5S,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-hydroxytetrahydro-2H-pyran-3,4-diyldibenzoate) more preferably in an amount in the range of from about 3 toabout 7 molar equivalents, for example, about 6 molar equivalents;

in a suitably selected organic solvent or mixture of organic solventssuch as DCM, CHCl₃, Et₂O, and the like; at a temperature in the range offrom about −50° C. to about room temperature, preferably at about −40°C. to about 20° C.; to yield the corresponding compound of formula(A-2).

Preferably the fluorinating agent is added to the mixture comprising thecompound of formula (A-1), at a rate which maintains the internaltemperature of the reaction mixture between 0° C. and room temperature(depending on the fluorinating agent as would be readily recognized bythose skilled in the art).

The compound of formula (A-2) is de-protected according to knownmethods, to remove the acyl groups. For example, the compound of formula(A-2) is reacted with a suitably selected base such as NaOCH₃,NaOCH₂CH₃, NaOH, KOH, and the like; wherein the base is preferablypresent in an amount in the range of from about 0.1 to about 3 molarequivalents, (relative to the molar amount of the compound of formula(A-2)), more preferably in an amount in the range of from about 0.4 toabout 2 molar equivalents, for example, about 0.5 molar equivalents; ina suitably selected organic solvent or mixture of organic solvents suchas methanol, ethanol, i-PrOH, MeOH/THF, 2-methyl-THF, and the like; toyield(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol.

The(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolis reacted with a suitably selected trialkyl silyl reagent such asTBDMSOTf, TBDMSCl, triethylsilyl chloride, triisopropylsilyl chloride,TBDPSCl, diethylisopropylsilyl chloride, isopropyldimethylsilylchloride, a known compound; wherein the trialkyl silyl reagent ispreferably present in an amount in the range of from about 1 to about 10molar equivalents, (relative to the molar amount of2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol),more preferably in an amount in the range of from about 3 to about 10molar equivalents, more preferably in an amount in the range of fromabout 5 to about 10 molar equivalents, for example, about 8 molarequivalents;

in the presence of a suitably selected organic base such as2,6-lutidine, 1H-imidazole, TEA, DIPEA, pyridine, and the like; whereinthe organic base is preferably present in an amount in the range of fromabout 1 to about 15 molar equivalents, (relative to the molar amount of2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol)more preferably in an amount in the range of from about 3 to about 15molar equivalents, more preferably in an amount in the range of fromabout 10 to about 15 molar equivalents, for example, about 12 molarequivalents; in a suitably selected organic solvent or mixture oforganic solvents such as DCM, 1,2-dichloroethane, DMF,dimethylacetamide, THF, acetonitrile, and the like; at a temperature inthe range of from about 0° C. to about 50° C., preferably at about roomtemperature; to yield the corresponding compound of formula (A-3)wherein A¹, A² and A³ are the corresponding alkyl groups (from thetrialkyl silyl reagent).

The compound of formula (A-3) is reacted with a suitably selectedO-allyl isomerization catalyst such as (PPh₃)₃RhCl, CpRu(CH₃CN)₃]PF₆(tris(acetonitrile)cyclopentadienylruthenium hexafluorophosphate),[{Ru(η³:η³-C₁₀H₁₆)Cl(μ-Cl)}₂], Fe(CO)₅,HRuCl(PPh₃)₃(chlorohydridotris(triphenylphosphine)ruthenium (II)complex) [Ir(Ph₂MeP)₂(cod)]⁺PF6⁻, (Ph₃P)₂CpRuCl, PdCl₂(PhCN)₂, and thelike; wherein the O-allyl isomerization catalyst is present in acatalytic amount, for example in an amount in the range of from about 1mole % to about 15 mole %, for example, about 10%; in the presence of asuitably selected organic base such as DABCO, DBU, Et₃NHPF₆(triethylammonium hexafluorophosphate), and the like; wherein theorganic base is preferably present in an amount in the range of fromabout 1 to about 3 molar equivalents, (relative to the molar amount ofthe compound of formula (A-3)), more preferably in an amount in therange of from about 1.5 to about 2.5 molar equivalents, for example,about 2 molar equivalents;

in a suitably selected organic solvent or mixture of water and a watermiscible organic solvent such as ethanol/water, i-PrOH/water, THF/water,and the like; at a temperature of in the range of from about 75° C. toabout 105° C., preferably at about reflux temperature; to yield thecorresponding compound of formula (A-4), wherein the compound of formula(A-4) is preferably not isolated. (One skilled in the art will recognizethat in this reaction step, the allyl group on the compound of formula(A-3) is isomerized to the corresponding vinyl group on the compound offormula (A-4)).

The compound of formula (A-4) is reacted with a suitably selectedco-oxidant such as NMO, NaHSO₃, benzoquinone, and the like; wherein theoxidizing agent is preferably present in an amount in the range of fromabout 1 to about 5 molar equivalents, (relative to the molar amount ofthe compound of formula (A-3)), more preferably in an amount in therange of form about 1 to about 2.5 molar equivalents, more preferably inan amount in the range of from about 1 to about 2 molar equivalents, forexample, about 1.5 molar equivalents; in the presence of a suitablyselected oxidizing reagent such as OsO₄, KMnO₄, NaIO₄, and the like;wherein the oxidizing reagent is preferably present in a catalyticamount, for example, in an amount in the range of from about 1 mole % toabout 20%, more preferably in an amount in the range of from about 1mole % to about 10 mole %, for example, about 5%; in a suitably selectedorganic solvent or mixture of water and a water miscible organic solventsuch as acetone/water, t-BuOH/water, acetone/t-BuOH/water, CH₃CN/water,DMSO/water, and the like; at a temperature in the range of from about 0°C. to about 50° C., preferably at a temperature in the range of fromabout 15° C. to about 40° C., more preferably at about 30° C.; to yieldthe corresponding compound of formula (A-5).

The compound of formula (A-5) is reacted with a suitably selectedoxidizing agent; to yield the corresponding compound of formula (V-S).In an example, the compound of formula (A-5) is reacted under SWERNoxidation conditions, e.g. with a suitably selected reagent such asacetic anhydride, trifluoromethyl acetic anhydride, oxalyl chloride,cyanuric chloride, pyridine-sulfur trioxide, and the like; wherein thereagent is preferably present in an amount in the range of from about 2to about 50 molar equivalents, (relative to the molar amount of thecompound of formula (A-5)) for example, about 25 molar equivalents; inDMSO; at a temperature in the range of from about −60° C. to about 30°C.; to yield the corresponding compound of formula (V-S). Alternatively,the compound of formula (A-5) is reacted with a suitably selectedoxidizing agent such as Dess-Martin periodinane, pyridiniumchlorochromate (preferably in DCM), and the like; in a suitably selectedorganic solvent such as DCM, 1,2-dichloroethane, and the like; to yieldthe corresponding compound of formula (V-S). Alternatively, the compoundof formula (A-5) is reacted with a suitably selected oxidizingagent/organic solvent combination such as Jones reagent in acetone,NaClO₂/TEMPO in DCM or AgCO₃ in benzene, and the like; to yield thecorresponding compound of formula (V-S).

The compound of formula (V-S) is preferably isolated (from the DMSO)and/or purified (e.g. by column chromatography or recrystallization)according to known methods, as would be readily recognized by thoseskilled in the art.

Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg to about1000 mg or any amount or range therein, and may be given at a dosage offrom about 0.05 mg/day to about 300 mg/day, or any amount or rangetherein, preferably from about 0.1 mg/day to about 100 mg/day, or anyamount or range therein, preferably from about 1 mg/day to about 50mg/day, or any amount or range therein. The dosages, however, may bevaried depending upon the requirement of the patients, the severity ofthe condition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from about 0.01 mg to about1,000 mg, or any amount or range therein, of the active ingredient ofthe present invention. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders mediated by SGLT activity, preferablydual SGLT1 and SGLT2 activity, described in the present invention mayalso be carried out using a pharmaceutical composition comprising any ofthe compounds as defined herein and a pharmaceutically acceptablecarrier. The pharmaceutical composition may contain between about 0.01mg and about 1000 mg of the compound, or any amount or range therein,preferably from about 0.05 mg to about 300 mg of the compound, or anyamount or range therein, more preferably from about 0.1 mg to about 100mg of the compound, or any amount or range therein, more preferably fromabout 0.1 mg to about 50 mg of the compound, or any amount or rangetherein; and may be constituted into any form suitable for the mode ofadministration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixers, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methylcellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders mediated by SGLT activity, preferablydual SGLT1 and SGLT2 activity, is required.

The daily dosage of the products may be varied over a wide range fromabout 0.01 mg to about 1,000 mg per adult human per day, or any amountor range therein. For oral administration, the compositions arepreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugmay be ordinarily supplied at a dosage level of from about 0.005 mg/kgto about 10 mg/kg of body weight per day, or any amount or rangetherein. Preferably, the range is from about 0.01 to about 5.0 mg/kg ofbody weight per day, or any amount or range therein, more preferably,from about 0.1 to about 1.0 mg/kg of body weight per day, or any amountor range therein, more preferably, from about 0.1 to about 0.5 mg/kg ofbody weight per day, or any amount or range therein. The compounds maybe administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Intermediate Synthesis Example A(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one

Step 1:(2S,3R,4S,5S,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-hydroxytetrahydro-2H-pyran-3,4-diyldibenzoate

To a solution of allyl alpha-D-galactopyranoside (5 g, 22.1 mmol) in drypyridine (80 ml) at −35° C.˜−30° C. was added benzoyl chloride (8.17 ml,70.4 mmol) dropwise with stirring. The reaction mixture was stirred atthat temperature for 20 min, then warmed to room temperature and stirredat room temperature for 8 h. The reaction mixture was then addeddropwise to an aqueous sodium bicarbonate solution (200 ml) at 0° C. Theresulting mixture was extracted with EtOAc three times (150 ml eachtime). The combined organic extracts were washed with 1N HCl twice, thenwashed once with brine, dried over Na₂SO₄, and concentrated underreduced pressure to yield a light orange oil. The isolated material wasdivided into two portions and each portion was dissolved in 6 ml of DCMand loaded onto an 80 g column—chromatography on silica gel(EtOAc/heptanes: 0>>>20%>>>30%) to yield a white solid. ¹H NMR(CHLOROFORM-d) δ: 8.07 (s, 1H), 8.04-8.06 (m, 1H), 7.97-8.02 (m, 4H),7.56-7.62 (m, 1H), 7.49-7.55 (m, 2H), 7.43-7.48 (m, 2H), 7.35-7.42 (m,4H), 5.77 (d, J=3.0 Hz, 2H), 5.72 (d, J=3.5 Hz, 1H), 5.12 (dd, J=10.6,1.5 Hz, 1H), 4.62-4.75 (m, 1H), 4.51-4.62 (m, 1H), 4.36-4.47 (m, 2H),4.21-4.31 (m, 1H), 3.99-4.16 (m, 1H). LC/MS m/z (M+Na)⁺554.8.

Step 2:(2S,3R,4R,5R,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diylDibenzoate

To a solution of(2S,3R,4S,5S,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-hydroxytetrahydro-2H-pyran-3,4-diyldibenzoate (1.47 g, 2.76 mmol) anhydrous DCM (15 mL) at −40° C. wasadded neat DAST (diethylaminosulfur trifluoride) (2.03 ml, 16.56 mmol)dropwise, and the resulting mixture was stirred at that temperature for30 min, then warmed to room temperature and stirred for 20 h. Theresulting mixture was slowly added to a dry-ice cooled MeOH (80 ml) andthe resulting mixture was stirred for 10 min, concentrated and theresidue was loaded onto a 40 g column and purified by flash columnchromatography (EtOAc/heptanes: 0>>>5%>>>15%) to yield a white foam. ¹HNMR (CHLOROFORM-d) δ: 8.06-8.17 (m, 2H), 7.93-8.04 (m, 4H), 7.57-7.66(m, 1H), 7.46-7.57 (m, 4H), 7.39 (td, J=7.6, 1.5 Hz, 4H), 6.08-6.24 (m,1H), 5.76-5.95 (m, 1H), 5.10-5.35 (m, 4H), 4.66-4.89 (m, 2H), 4.56-4.65(m, 1H), 4.33-4.44 (m, 1H), 4.22-4.33 (m, 1H), 4.03-4.14 (m, 1H).

Step 3:(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

To a suspension of(2S,3R,4R,5R,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diyldibenzoate (3.4 g, 6.36 mmol) in anhydrous MeOH (100 ml) was added 25%NaOMe in MeOH (0.5 mL) dropwise and the resulting mixture was stirred atroom temperature for 16 h. The base was neutralized with Dowex 50WX8(H⁺) ion-exchange resin, filtered and the filtrate was concentrated andthe residue was purified by flash column chromatography on silica gel(12 g column, EtOAc) to yield a white foam (initially a colorlesssyrup). ¹H NMR (METHANOL-d₄) δ: 5.97 (ddt, J=16.9, 11.1, 5.5 Hz, 1H),5.35 (dd, J=17.2, 1.5 Hz, 1H), 5.19 (dd, J=10.4, 1.3 Hz, 1H), 4.82-4.87(m, 1H), 3.99-4.35 (m, 4H), 3.89 (dt, J=16.4, 9.0 Hz, 1H), 3.63-3.81 (m,3H), 3.43 (dd, J=9.9, 3.8 Hz, 1H).

Step 4:(((2S,3R,4R,5R,6R)-2-(allyloxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane)

To a cooled (0° C.) mixture of(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(519.8 mg, 2.339 mol) and 2,6-lutidine (3.3 ml, 28.1 mmol) in anhydrousdichloromethane (10 ml) was added tert-BuMe₂SiOTf (4.4 ml, 18.7 mmol).The reaction mixture was warmed to room temperature and stirred for 10min, then kept stirring at 40° C. for 2 days, allowed to cool, and thendiluted with DCM (70 ml). The reaction mixture was washed with aq.NaHCO₃, dried with Na₂SO₄, and concentrated under reduced pressure toyield a light brown oil, which was purified by flash columnchromatography on silica gel (EtOAc/heptane: 0>>>5%) to yield acolorless oil. ¹H NMR (CHLOROFORM-d) δ: 5.85 (br d, J=5.1 Hz, 1H), 5.21(dd, J=17.2, 1.5 Hz, 1H), 5.11 (d, J=10.1 Hz, 1H), 4.70 (t, J=3.3 Hz,1H), 3.85-4.19 (m, 4H), 3.74-3.82 (m, 1H), 3.62-3.73 (m, 2H), 3.44 (dd,J=9.1, 3.5 Hz, 1H), 0.74-0.88 (m, 18H), −0.05-0.07 (m, 18H).

Step 5:(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol

[(Ph₃P)₃RhCl] (195.1 mg, 0.211 mmol) and DABCO (481.6 mg, 4.29 mmol)were added to a 50 ml round-bottle flask under argon. To the flask wasthen added a EtOH/H₂O (10:1 v/v) solution of(((2S,3R,4R,5R,6R)-2-(allyloxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane)(22 ml, 1617 mg, 2.86 mmol) and the resulting mixture was heated underreflux for 16 h (overnight), then diluted with DCM (80 ml) and washedwith saturated aqueous NaHCO₃ (20 ml) and brine (15 ml). The solventswere removed under reduced pressure. The resulting residue was dissolvedin acetone/H₂O (10:1 v/v, 22 ml). NMO (415 mg, 3.44 mmol) and OsO₄ (220uL, 4% solution in water) were added and the reaction was monitored byTLC (starting material: top spot, Rf ˜0.85/Eluent: EtOAc/heptane: 1/8v/v; desired product: Rf ˜0.25/eluent: EtOAc/heptane: 1/8 v/v, for thisscale, reaction time: 5 h). The reaction mixture was concentrated underreduced pressure and the residue was diluted with DCM (80 ml) and washedwith saturated aqueous NaHCO₃ (20 ml) and brine (15 ml). The organiclayer was dried with Na₂SO₄ and the solvent was removed under reducedpressure. The residue was purified by flash column chromatography onsilica gel (EtOAc/heptane: 0>>>5%>>>10%) to yield a colorless syrup. ¹HNMR (CHLOROFORM-d) δ: 5.03-5.17 (m, 1H), 4.15-4.39 (m, 1H), 3.73-4.03(m, 4H), 3.54 (dd, J=8.6, 3.5 Hz, 1H), 2.93 (br s, 1H), 0.83-0.97 (m,18H), 0.06-0.18 (m, 18H). LC/MS m/z (M+Na)⁺: 547.05.

Step 6:(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one

(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(856.1 mg, 1.63 mmol) was dissolved in DMSO (4.3 ml) and stirred at roomtemperature for 10 min. To the resulting solution was then added aceticanhydride (3 ml) dropwise at room temperature. The mixture was stirredat room temperature for 24 h, diluted with EtOAc, washed with ice-waterand aq. NaHCO₃ solution, dried with Na₂SO₄. The resulting residue waspurified by flash column chromatography on silica gel (40 g column,EtOAc/heptane: 0>>>5%) to yield a colorless syrup, which was solidifiedin vacuo to yield the title compound as a white crystal.

¹H NMR (CHLOROFORM-d) δ: 4.54-4.69 (m, 1H), 4.51-4.54 (m, 1H), 3.88-4.00(m, 2H), 3.79-3.86 (m, 1H), 3.68-3.76 (m, 1H), 0.74-0.82 (m, 18H),−0.08-0.05 (m, 18H).

Intermediate Synthesis Example B(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one

Step 1:(3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluorotetrahydro-2H-pyran-2,3,4-triylTriacetate

To a mixture of(3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4-triol(3.00 g, 16.5 mmol) and sodium acetate (1.90 g, 23.1 mmol) was addedacetic anhydride (90 mL) and the suspension was heated at 100° C. andstirred at this temperature for 2 h, then cooled to room temperature andstirred at room temperature for 6 h. Evaporation of the mixture yieldeda residue which was crystallized in methanol to yield a white solid. ¹HNMR (CHLOROFORM-d) δ: 5.67-5.79 (m, 1H), 5.30-5.47 (m, 1H), 5.01-5.16(m, 1H), 4.39 (br s, 2H), 4.21-4.32 (m, 1H), 3.82-3.93 (m, 1H),2.10-2.16 (m, 9H), 2.05 (s, 3H).

Step 2:(2R,3R,4R,5R,6R)-6-(acetoxymethyl)-2-bromo-5-fluorotetrahydro-2H-pyran-3,4-diylDiacetate

A mixture of1,2,3,6-tetra-O-acetyl-4-deoxy-4-fluoro-alpha-D-galactopyranoside (3.52g, 10.1 mmol) in a solution of 33% HBr-HOAc was stirred at roomtemperature for 3 h. The mixture was concentrated under reduced pressureto yield an oily product, which was used for the next step reactionwithout further purification. ¹H NMR (CHLOROFORM-d) δ: 6.42-6.65 (m,1H), 5.56-5.82 (m, 1H), 4.70-4.86 (m, 1H), 4.26-4.68 (m, 4H), 2.09-2.18(m, 9H).

Step 3:(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diylDiacetate

A mixture of 2,3,6-tri-O-acetyl-a-D-glucopyranosylbromide (3.73 g, 10.1mmol based) and Et₃N (5.6 ml, 40.2 mmol) were dissolved indichloromethane (100 mL). Thereafter p-thiocresol (2.55 g, 20.1 mmol)was added and the reaction mixture was stirred at room temperature for16 h. The solid was filtered, then washed with dichloromethane threetimes. The filtrate was concentrated under reduced pressure and theresulting residue was purified by flash column chromatography on silicagel (40 g COMBIFLAS® column, EtOAc/heptane: 0>>>5%>>>30%) to yield awhite solid. ¹H NMR (CHLOROFORM-d) δ: 7.33-7.44 (m, 2H), 7.05-7.19 (m,2H), 5.25-5.42 (m, 1H), 4.83-4.93 (m, 1H), 4.61-4.71 (m, 1H), 4.31-4.55(m, 2H), 4.19-4.28 (m, 1H), 3.67-3.83 (m, 1H), 2.35 (s, 3H), 2.05-2.15(m, 9H). LC/MS: m/z (M+Na): 436.80.

Step 4:(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diol

(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diyldiacetate (1.90 g, 4.58 mmol) was suspended in anhydrous MeOH (60 mL).Sodium methoxide (25% methanol solution, 10 drops) was added and theresulting mixture was stirred at room temperature for 16 h. The base wasneutralized with Dowex 50WX8 (H+) ion-exchange resin, the resultingsuspension was filtered, and the filtrate was concentrated to yield awhite crystalline solid. ¹H NMR (METHANOL-d₄) δ: 7.46 (brd, J=8.1 Hz,2H), 7.13 (s, 2H), 4.51-4.61 (m, 1H), 4.06-4.36 (m, 1H), 3.75-3.88 (m,1H), 3.60-3.73 (m, 2H), 3.48 (td, J=4.7, 2.3 Hz, 1H), 3.22 (t, J=9.3 Hz,1H), 2.30 (s, 3H). LC/MS: m/z (M+Na)⁺: 310.8.

Step 5:(2S,3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran

To a mixture of(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diol(1.27 g, 4.41 mmol), sodium hydride (1.06 g, 26.4 mmol) and n-Bu₄NI(tetrabutylammonium iodide) (1.63 g, 4.41 mmol) was added anhydrous DMF(55 mL) under argon atmosphere at 0° C. and the resulting mixture wasstirred at that temperature for 20 min. Neat benzyl bromide (2.5 mL) wasthen added dropwise and the reaction mixture was allowed to warm to roomtemperature, then kept stirring for 16 h. The resulting mixture wasdiluted with dichloromethane and aq. NH₄Cl. The water layer wasextracted with dichloromethane twice and the combined organic extractswere washed with brine, then dried with Na₂SO₄, filtered andconcentrated under reduced pressure to yield an oily product, which waspurified by flash column chromatography on silica gel (120 g COMBIFLASH®column, EtOAc/heptane: 0>>>5%) to yield a white solid. ¹H NMR(CHLOROFORM-d) δ: 7.46 (d, J=8.1 Hz, 2H), 7.26-7.44 (m, 15H), 7.03 (d,J=8.1 Hz, 2H), 4.82-4.93 (m, 2H), 4.77 (s, 2H), 4.40-4.67 (m, 4H),3.67-3.90 (m, 3H), 3.55-3.65 (m, 1H), 3.44 (s, 1H), 2.30 (s, 3H).

Step 6:(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol

To a solution of(2S,3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran(2390 mg, 4.28 mmol) in acetone-H₂O (9:1, 40 ml) was added NBS (1.52 g,8.56 mmol) and the mixture was stirred at room temperature. Aftercompletion as measured by TLC analysis), the reaction mixture wasevaporated to dryness, diluted with Na₂SO₃, and extracted with EtOAc.The organic layer was washed with brine, dried with Na₂SO₄ andconcentrated to yield a colorless oil which was further purified byflash column chromatography on silica gel (80 g AnaLogix column,EtOAc/heptane: 0>>>10%>>>35%) to yield a syrup.

Step 7:(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one

(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(1.50 g, 3.32 mmol) was dissolved in DMSO (8.7 ml) and stirred at 0° C.for 10 min. To the resulting solution was added acetic anhydride (6 ml)at 0° C. under argon atmosphere. The mixture was then stirred at roomtemperature for 16 h. Ice-water was added and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with coldwater twice and then dried with Na₂SO₄. The filtrate was concentratedand the residue was purified by flash column chromatography on silicagel (40 g COMBIFLASH® column, EtOAc/heptane: 0>>>5%>>>15%) to yield thetitle compound as a white solid.

¹H NMR (CHLOROFORM-d) δ: 7.28-7.41 (m, 15H), 4.92 (s, 2H), 4.50-4.75 (m,6H), 4.11-4.21 (m, 1H), 3.91-4.07 (m, 1H), 3.69-3.85 (m, 2H). LC/MS: m/z(M+Na)⁺: 472.95.

Synthesis Example 1: Compound #9(2S,3R,4R,5S,6R)-2-[5-(1-benzothiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl]-5-fluoro-6-(methoxymethyl)oxane-3,4-diol

To a mixture of(3R,4S,5R,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (50g, 277.54 mmol, 1.00 equiv) in DMF (500 mL) with(dimethoxymethyl)benzene (50 mL, 1.10 equiv) was added TsOH (800 mg,4.65 mmol, 0.20 equiv) and the reaction was stirred for 3 h at 60° C.Sodium bicarbonate was added, the resulting mixture was concentrationand then extracted with DCM thrice. The combined extracts were washedwith brine and dried over Na₂SO₄. The resulting residue was concentratedand purified by chromatography on silica gel (10:1 DCM/MeOH) to yield(4aR,7R,8R,8aR)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6,7,8-triolas yellow oil.

To a mixture of(4aR,7R,8R,8aR)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6,7,8-triol(80 g, 298.22 mmol, 1.00 equiv) in DMF (1000 mL) was added NaH (72 g,1.80 mol, 6.00 equiv) in portions and the mixture stirred for 30 min at0° C. To the resulting solution was then added BnBr (304.5 g, 1.78 mol,6.00 equiv) dropwise at 0° C., and the reaction was stirred forovernight at room temperature. MeOH was added to quench the reaction at0° C., and the resulting mixture was then diluted with water (2000 mL),and extracted with ethyl acetate thrice. The combined extracts werewashed with brine and dried over Na₂SO₄, The mixture was thenconcentrated and purified by chromatography on silica gel (10:1 PE/EA)to yield(4aR,7R,8S,8aS)-6,7,8-tris(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxineas white solid. MS (ES) m/z: 556 [M+NH₄]⁺

To a mixture of(4aR,7R,8S,8aS)-6,7,8-tris(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine(9 g, 16.71 mmol, 1.00 equiv) in 1,4-dioxane (90 mL) was added 3N HCl(90 mL), and the reaction was stirred for 4 h at 100° C. Water was addedand the mixture was extracted with DCM thrice. The combined extractswere washed with water, brine and dried over Na₂SO₄, The mixture wasthen concentrated and purified by chromatography on silica gel (10:1DCM/MeOH) to yield(3R,4S,5S,6R)-3,4-bis(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diolas yellow solid. MS (ES) m/z: 383 [M+Na]⁺

To a mixture of(3R,4S,5S,6R)-3,4-bis(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diol(2.45 g, 6.80 mmol, 1.00 equiv) in DCM (20 mL) was added NIS (3 g, 13.45mmol, 2.00 equiv) and TBAl (750 mg, 2.03 mmol, 0.30 equiv), and thereaction was stirred for overnight at 25° C. NaHSO₃/H₂O was added andthe mixture was extracted with DCM thrice. The combined extracts werewashed with brine and dried over Na₂SO₄, The mixture was thenconcentrated and purified by chromatography on silica gel (10:1DCM/MeOH) to yield(3R,4S,5S,6R)-3,4-bis(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-oneas yellow solid. MS (ES) m/z: 376 [M+NH₄]⁺

To a mixture of(3R,4S,5S,6R)-3,4-bis(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one(6.8 g, 18.97 mmol, 1.00 equiv) in THF (40 mL) with NMM(N-methylmorpholine) (6.7 g, 66.24 mmol, 3.50 equiv) was added TMSCl(trimethylsilyl chloride) (6.15 g, 56.61 mmol, 3.00 equiv) dropwise at0° C., and the reaction was stirred for overnight at 30° C. Water wasadded and the mixture was extracted with ethyl acetate thrice. Thecombined extracts were washed with NaH₂PO₄/H₂O, brine and dried overNa₂SO₄, then concentration and purified by chromatography on silica gel(10:1 PE/EA) to yield(3R,4R,5S,6R)-3,4-bis(benzyloxy)-5-((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-oneas light yellow oil.

To a mixture of2-(4-(benzyloxy)-5-bromo-2-methoxybenzyl)benzo[b]thiophene (4.26 g, 9.70mmol, 1.10 equiv) in tetrahydrofuran (50 mL) was added n-BuLi (4.2 mL,1.15 equiv) dropwise at −78° C. and the mixture was stirred for 25 min.to the mixture was then added(3R,4R,5S,6R)-3,4-bis(benzyloxy)-5-((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one(4.44 g, 8.83 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise at−78° C. The solution was stirred at −78° C. for 1.5 h, and then MeSO₃H(1.3 mL, 20 mmol) in MeOH (20 mL) was added, the reaction was stirredovernight at room temperature. H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄, The mixture was then concentrated andpurified by chromatography on silica gel (1:1 PE/EA) gave 4.5 g (69.6%)of(2R,3S,4S,5R)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3-olas yellow oil. MS (ES) m/z: 701 [M-OMe]⁺

To a mixture of(2R,3S,4S,5R)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3-ol(6.5 g, 8.87 mmol, 1.00 equiv) in dichloromethane (50 mL) with Et₃SiH(2.1 g, 18.06 mmol, 2.00 equiv) was added BF₃.Et₂O (1.9 g, 13.38 mmol,1.50 equiv) at 0° C. The reaction was stirred for 2 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄, The mixture was then concentrated and purified bychromatography on silica gel (1:1 PE/EA) gave 4.6 g (73.9%) of(2R,3S,4S,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-olas yellow oil. MS (ES) m/z: 720 [M+NH₄]⁺

To a mixture of(2R,3S,4S,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol(2.3 g, 3.27 mmol, 1.00 equiv) in pyridine (20 mL) was added TrCl(triphenylmethyl chloride)(1.1 g, 3.96 mmol, 1.20 equiv). The reactionwas stirred for overnight at 90° C. The mixture was then concentrated toremove the pyridine. H₂O was added and the mixture was extracted withethyl acetate thrice. The combined extracts were washed with brine anddried over Na₂SO₄, The mixture was then concentrated and purified bychromatography on silica gel (3:1 PE/EA) to yield(2R,3S,4S,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-2-((trityloxy)methyl)tetrahydro-2H-pyran-3-olas yellow solid.

To a mixture of(2R,3S,4S,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-2-((trityloxy)methyl)tetrahydro-2H-pyran-3-ol(200 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL) was added asolution of DAST (100 mg, 0.62 mmol, 3.00 equiv) in DCM (0.5 ml)dropwise at −30° C. The reaction was stirred for 3 h at roomtemperature. Sodium bicarbonate/H₂O was added and the mixture wasextracted with dichloromethane thrice. The combined extracts were washedwith brine and dried over Na₂SO₄, The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-((trityloxy)methyl)tetrahydro-2H-pyranas colorless oil. MS (ES) m/z: 964 [M+NH₄]⁺

To a mixture of(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-((trityloxy)methyl)tetrahydro-2H-pyran(168 mg, 0.177 mmol, 1.00 equiv) in dichloromethane/MeOH (5/5 mL) wasadded AcCl (acetyl chloride) (0.1 ml). The reaction was stirred for 2 hat room temperature. Sodium bicarbonate/H₂O was added and the mixturewas extracted with dichloromethane thrice. The combined extracts werewashed with brine and dried over Na₂SO₄, The mixture was thenconcentrated and purified by chromatography on silica gel (2:1 PE/EA) toyield((2R,3R,4R,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methanolas light yellow oil. MS (ES) m/z: 722 [M+NH₄]⁺

To a mixture of((2R,3R,4R,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methanol(100 mg, 0.14 mmol, 1.00 equiv) in DMF (5 mL) with KOH (25 mg, 0.45mmol, 3.00 equiv) was added CH₃1 (60 mg, 0.42 mmol, 3.00 equiv). Thereaction was stirred for 5 h at room temperature. H₂O was added and themixture was extracted with EA thrice. The combined extracts were washedwith brine and dried over Na₂SO₄, The mixture was then concentrated andpurified by chromatography on silica gel (2:1 PE/EA) to yield(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-(methoxymethyl)tetrahydro-2H-pyranas a yellow oil.

To a mixture of(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-(methoxymethyl)tetrahydro-2H-pyran(100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (200 mg, 1.35 mmol, 9.65 equiv) was addedBCl₃ (2 mL, 14.3 equiv, 1 N) at −78° C. The reaction was stirred at −78°C. for 1 h. Methanol (2 mL) was added and the resulting mixtureconcentrated, the residue purified by chromatography on Prep-HPLC(0%-45% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl)-5-fluoro-6-(methoxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, Methanol-d₄) δ: 7.72 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.18-7.42 (m, 3H), 7.00 (s, 1H), 6.50 (s, 1H), 4.59 (d, J=9.6Hz, 1H), 4.45 (t, J=18 Hz, 0.5H), 4.28 (t, J=18 Hz, 0.5H), 4.13 (s, 2H),3.83 (s, 3H), 3.54-3.80 (m, 5H), 3.34 (s, 3H). MS (ES) m/z: 471[M+Na]⁺

Synthesis Example 2: Compound #11(2S,3R,4R,5S,6R)-2-[5-(1-benzothiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl]-5-fluoro-6-(fluoromethyl)oxane-3,4-diol

To a mixture of((2R,3R,4R,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methanol(100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (5 mL) was added asolution of DAST (68.6 mg, 0.43 mmol, 3.00 equiv) in DCM (0.5 ml)dropwise at −30° C. The reaction was stirred for 3 h at roomtemperature. Sodium bicarbonate/H₂O was added and the mixture wasextracted with dichloromethane thrice. The combined extracts were washedwith brine and dried over Na₂SO₄, The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield1-((2S,3S,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4-(benzyloxy)-5-fluoro-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)-1I3-oxaspiro[2.5]octa-3(8),4,6-trieneas yellow oil.

To a mixture of1-((2S,3S,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-4-(benzyloxy)-5-fluoro-6-(fluoromethyl)tetrahydro-2H-pyran-3-yl)-1I3-oxaspiro[2.5]octa-3(8),4,6-triene(100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (200 mg, 1.35 mmol, 9.65 equiv) was addedBCl₃ (2 mL, 14.3 equiv, 1 N) at −78° C. The reaction was stirred at −78°C. for 1 h. Methanol (2 mL) was added. The resulting mixture wasconcentrated and purified by chromatography on Prep-HPLC (0%-45%CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl)-5-fluoro-6-(fluoromethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, Methanol-d₄) δ: 7.72 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8Hz, 1H), 7.19-7.30 (m, 3H), 7.00 (s, 1H), 6.51 (s, 1H), 4.71 (s, 1H),4.65 (d, J=9.6 Hz, 1H), 4.55 (s, 1H), 4.50 (t, J=18.6 Hz, 0.5H), 4.33(t, J=18.3 Hz, 0.5H), 4.14 (d, J=5.4 Hz, 2H), 3.83-3.73 (m, 5H),3.59-3.65 (m, 1H). MS (ES) m/z: 459 [M+Na]⁺.

Synthesis Example 3: Compound #2(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

Into a 500-mL round-bottom flask, was placed a solution of2,4-dihydroxybenzaldehyde (25 g, 181.00 mmol, 1.00 equiv) in dry CH₃CN(200 mL), sodium bicarbonate (20 g, 238.08 mmol, 1.30 equiv) and KI (3g, 18.10 mmol, 0.10 equiv) at room temperature under an nitrogenatmosphere. The mixture was slowly warmed to 60° C., followed byaddition of (chloromethyl)benzene (27.5 g, 217.25 mmol, 1.20 equiv). Theresulting solution was heated to reflux for 16 h, cooled and the solidswere filtered out. The resulting mixture was concentrated under vacuum.The mixture was washed by 2×100 ml PE:EA (1:20) to yield4-(benzyloxy)-2-hydroxybenzaldehyde as a yellow solid.

Into a 250-mL round-bottom flask, was placed a solution of4-(benzyloxy)-2-hydroxybenzaldehyde (12.7 g, 55.64 mmol, 1.00 equiv) inMeOH (150 mL). This was followed by the addition of pyridine perbromidehydrobromide (18.6 g, 58.49 mmol, 1.05 equiv) in several batches at 0°C. The resulting solution was stirred overnight at 25° C., monitored byTLC (EA:PE=1:5), and the reaction terminated by addition of water (50mL). The MeOH was removed under vacuum. The resulting solution wasdiluted with water (200 mL). The resulting solution was extracted withethyl acetate (3×100 mL) and the organic layers were combined. Theresulting mixture was washed with 1N HCl (1×100 mL) and water (1×100mL). The resulting mixture was washed with brine (1×100 mL). The mixturewas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was washed by 2×50 ml PE:EA=1:20 to yield4-(benzyloxy)-5-bromo-2-hydroxybenzaldehyde as a yellow solid.

Into a 500-mL round-bottom flask, was placed a solution of4-(benzyloxy)-5-bromo-2-hydroxybenzaldehyde (13 g, 42.33 mmol, 1.00equiv) in N,N-dimethylformamide (100 mL), KOH (2.855 g, 50.89 mmol, 1.20equiv), iodomethane (18.1 g, 127.52 mmol, 3.00 equiv). The resultingsolution was stirred 3-4 h at room temperature. The reaction was thenquenched by the addition of water (200 mL). The resulting solution wasextracted with ethyl acetate (2×100 mL) and the organic layers combined. The resulting mixture was washed with water (1×200 mL) and brine(1×100 mL), dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was washed by 2×50 ml PE:EA=1:10 to yield4-(benzyloxy)-5-bromo-2-methoxybenzaldehyde as a yellow solid.

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of 1-benzothiophene(6 g, 44.71 mmol, 1.10 equiv) in tetrahydrofuran (100 mL). This wasfollowed by the addition of (2.5M in hexane) butyllithium (18.7 mL, 1.15equiv) dropwise with stirring at −78° C. The resulting mixture wasstirred 20 min at −78° C. To the mixture was then added a solution of4-(benzyloxy)-5-bromo-2-methoxybenzaldehyde (13 g, 40.48 mmol, 1.00equiv) in tetrahydrofuran (30 mL) dropwise with stirring at −78° C. Theresulting solution was stirred at −78° C. for 1 h. The reaction was thenquenched by the addition of NH₄Cl/H₂O (100 mL), extracted with ethylacetate (3×100 mL). The combined organic layer was washed with brine(2×100 mL), dried over anhydrous sodium sulfate, and concentrated undervacuum to yield1-benzothiophen-2-yl[4-(benzyloxy)-5-bromo-2-methoxyphenyl]methanol as ayellow oil.

Into a 500-mL round-bottom flask, was placed a solution of1-benzothiophen-2-yl[4-(benzyloxy)-5-bromo-2-methoxyphenyl]methanol (19g) in dichloromethane (200 mL), triethylsilane (9.5 g, 82.54 mmol),trifluoroacetic acid (9.5 g, 83.32 mmol) was added into at 0° C. Theresulting solution was stirred for 2 h at room temperature. The reactionmixture was then quenched by the addition of NaHCO₃/H₂O (100 mL) and theaqueous layer was extracted with DCM (2×100 mL) and the combined organiclayer was washed with brine (1×100 mL), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was washed by 2×50ml PE:EA=1:20 to yield2-[[4-(benzyloxy)-5-bromo-2-methoxyphenyl]methyl]-1-benzothiophene as ayellow solid.

To a mixture of2-[[4-(benzyloxy)-5-bromo-2-methylphenyl]methyl]-1-benzothiophene (245.4mg, 0.58 mmol, 1.00 equiv) in THF (3 mL) was added n-BuLi (2.5 M inhexane, 0.233 mL, 1.00 equiv) dropwise at −78° C. The reaction wasstirred for 30 min at −78° C. To this was added a solution of thecompound prepared in Intermediate Synthesis Example B (261 mg, 0.58mmol, 1.00 equiv) in THF (2 mL) dropwise at −78° C. The reaction wasstirred for 2 h at −78° C. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield(3R,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-olas yellow oil.

To a mixture of(3R,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(348 mg, 0.58 mmol, 1.00 equiv) in DCM/CH₃CN (3/3 mL) with Et₃SiH (202.3mg, 1.74 mmol, 3.00 equiv) was added BF₃.Et₂O (165.1 mg, 1.16 mmol, 2.00equiv) dropwise at 0° C. The reaction was stirred for 2 h at 0° C.Sodium bicarbonate was added and the mixture was extracted with DCMthrice. The combined extracts were washed with brine and dried overNa₂SO₄. The mixture was then concentrated and purified by chromatographyon silica gel (10:1 PE/EA) to yield(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyranas a yellow oil.

To a mixture of(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methoxyphenyl)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran(327 mg, 0.41 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (551 mg, 3.72 mmol, 9.08 equiv) was addedBCl₃ (5.5 mL, 13.3 equiv, 1 N) with stirring at −78° C. The reaction wasstirred at −78° C. for 1 h. Methanol was added. The reaction mixture wasThe mixture was then concentrated and purified by chromatography onsilica gel (10:1 DCM/MeOH) to yield(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methoxyphenyl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas white solid.

¹H NMR (300 MHz, Methanol-d₄) δ: 7.70 (d, J=7.80 Hz, 1H), 7.62 (d, J=9.0Hz, 1H), 7.23 (m, 3H), 6.98 (s, 1H), 6.50 (s, 1H), 4.57 (d, J=9.6 Hz,1H), 4.36 (dt, J=51.3 and 9.6 Hz, 1H), 4.12 (s, 2H), 3.57-3.85 (m, 8H).MS (ES) m/z: 457.0 [M+Na]⁺.

Synthesis Example 4: Compound #16(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methylphenyl)-5-fluoro-6-methyl-tetrahydro-2H-pyran-3,4-diol

To a mixture of(3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4-triol(10 g, 54.90 mmol, 1.00 equiv) in acetic anhydride (200 mL) was addedNaOAc (5.68 g, 69.27 mmol, 1.26 equiv) at room temperature. The reactionwas stirred for 3 h at 160° C. The mixture was then concentrated. Ethylacetate/brine was added and the mixture was extracted with EtOAc thrice.The combined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (2:1 PE/EA) to yield(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluorotetrahydro-2H-pyran-2,3,4-triyltriacetate as a white solid.

To a solution of HBr/HAc (40 mL) was added(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluorotetrahydro-2H-pyran-2,3,4-triyltriacetate (3.17 g, 9.05 mmol, 1.00 equiv). The reaction was stirred atroom temperature for 1 h. H₂O was added and the mixture was extractedwith EtOAc thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (2:1 PE/EA) to yield(2R,3R,4R,5R,6R)-6-(acetoxymethyl)-2-bromo-5-fluorotetrahydro-2H-pyran-3,4-diyldiacetate as a yellow oil.

To a mixture of(2R,3R,4R,5R,6R)-6-(acetoxymethyl)-2-bromo-5-fluorotetrahydro-2H-pyran-3,4-diyldiacetate (12.5 g, 33.68 mmol, 1.00 equiv) in DMF (120 mL) with K₂CO₃(13.9 g, 100.57 mmol, 3.00 equiv) was added 4-methylbenzene-1-thiol(8.35 g, 67.23 mmol, 2.00 equiv) at room temperature. The reaction wasstirred at room temperature for 1 h. H₂O was added and and the mixturewas extracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄, The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diyldiacetate as a brown solid. MS (ES) m/z: 437 [M+Na]⁺.

To a mixture of(2S,3R,4R,5R,6R)-6-(acetoxymethyl)-5-fluoro-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diyldiacetate (3.2 g, 7.72 mmol, 1.00 equiv) in MeOH (30 mL) was added NaOMe(cat.) at room temperature. The reaction was stirred for overnight atroom temperature. Dowex 50wx 8-200 ion-exchange resin was added and themixture was filtrated. The filtrate was concentrated to yield(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diolas a yellow solid. ¹H NMR (300 MHz, CDCl₃) b 7.42 (d, J=8.1 Hz, 2H),7.16 (d, J=8.1 Hz, 2H), 4.52 (d, J=9.6 Hz, 1H), 4.45 (t, J=18.3 Hz,0.5H), 4.28 (t, J=18.6 Hz, 0.5H), 3.73-3.96 (m, 3H), 3.49-3.58 (m, 1H),3.28-3.39 (m, 1H), 2.35 (s, 3H). MS (ES) m/z: 311 [M+Na]⁺.

To a mixture of(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diol(200 mg, 0.690 mmol, 1.00 equiv) in pyridine (2 mL) was added TsCl(4-toluenesulfonyl chloride) (158.3 mg, 0.83 mmol, 1.20 equiv) at roomtemperature. The reaction was stirred for overnight at room temperature.After concentrated, ethyl acetate was added and the mixture was washedwith 1N HCl, brine and dried over Na₂SO₄. The mixture was The mixturewas then concentrated and purified by chromatography on silica gel (20:1DCM/MeOH) to yield((2R,3S,4R,5R,6S)-3-fluoro-4,5-dihydroxy-6-(p-tolylthio)tetrahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate as a yellow oil.

To a mixture of((2R,3S,4R,5R,6S)-3-fluoro-4,5-dihydroxy-6-(p-tolylthio)tetrahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate (470 mg, 1.06 mmol, 1.00 equiv) intetrahydrofuran (10 mL) was added LiAlH₄ (121.3 mg, 3.20 mmol, 3.00equiv). The reaction was heated to reflux for 1 h. Water/ice was added.The mixture was The mixture was then concentrated and purified bychromatography on silica gel (1:1 PE/EA) to yield(2S,3R,4R,5S,6R)-5-fluoro-6-methyl-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diolas a yellow oil.

To a mixture of(2S,3R,4R,5S,6R)-5-fluoro-6-methyl-2-(p-tolylthio)tetrahydro-2H-pyran-3,4-diol(270 mg, 0.99 mmol, 1.00 equiv) in DMF (5 mL) with BnBr (1.02 g, 5.96mmol, 6.00 equiv) was added NaH (160 mg, 4.00 mmol, 4.00 equiv, 60%purity). The reaction was stirred for overnight at room temperature. Icewater was added and the mixture was extracted with EtOAc twice. Thecombined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (10:1 PE/EA) to yield(2S,3R,4R,5R,6R)-3,4-bis(benzyloxy)-5-fluoro-6-methyl-2-(p-tolylthio)tetrahydro-2H-pyranas a yellow oil.

To a mixture of(2S,3R,4R,5R,6R)-3,4-bis(benzyloxy)-5-fluoro-6-methyl-2-(p-tolylthio)tetrahydro-2H-pyran(343 mg, 0.76 mmol, 1.00 equiv) in acetone/H₂O (5/0.5 mL) was added NBS(405.2 mg, 2.28 mmol, 3.00 equiv) at room temperature. The reaction wasstirred at room temperature for 2 h. Ice water was added and the mixturewas extracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran-2-olas a yellow oil.

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran-2-ol(240 mg, 0.69 mmol, 1.00 equiv) in DMSO (5 mL) was added aceticanhydride (2 mL) dropwise at room temperature. The reaction was stirredfor overnight at room temperature. Ice water was added and the mixturewas extracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (10:1 PE/EA) to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran-2-oneas a yellow oil.

To a mixture of2-[[4-(benzyloxy)-5-bromo-2-methylphenyl]methyl]-1-benzothiophene (245.4mg, 0.58 mmol, 1.00 equiv) in THF (3 mL) was added n-BuLi (2.5 M inhexane, 0.233 mL, 1.00 equiv) dropwise at −78° C. The reaction wasstirred for 30 min at −78° C. To this was added a solution of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran-2-one(200 mg, 0.58 mmol, 1.00 equiv) in THF (2 mL) dropwise at −78° C. Thereaction was stirred for 2 h at −78° C. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (5:1 PE/EA) toyield(3R,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran-2-olas a yellow oil.

To a mixture of(3R,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran-2-ol(400 mg, 0.58 mmol, 1.00 equiv) in DCM/CH₃CN (3/3 mL) with Et₃SiH (202.3mg, 1.74 mmol, 3.00 equiv) was added BF₃.Et₂O (165.1 mg, 1.16 mmol, 2.00equiv) dropwise at 0° C. The reaction was stirred for 2 h at 0° C.Sodium bicarbonate was added and the mixture was extracted with DCMthrice. The combined extracts were washed with brine and dried overNa₂SO₄. The mixture was then concentrated and purified by chromatographyon silica gel (10:1 PE/EA) to yield(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyranas a yellow oil.

To a mixture of(2S,3S,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-methyltetrahydro-2H-pyran (100 mg,0.15 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (200 mg, 1.35 mmol, 9.08 equiv) was addedBCl₃ (2 mL, 13.3 equiv, 1 N) with stirring at −78° C. The reaction wasstirred at −78° C. for 1 h. Methanol was added. The mixture was thenconcentrated and purified by chromatography on silica gel (10:1DCM/MeOH) to yield(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methylphenyl)-5-fluoro-6-methyltetrahydro-2H-pyran-3,4-diolas a white solid.

¹H-NMR: (400 MHz, CD₃OD) δ: 7.72 (d, J=7.6 Hz, 1H), 7.62 (d, J=8.0 Hz,1H), 7.20-7.29 (m, 3H), 6.91 (s, 1H), 6.69 (s, 1H), 4.60 (d, J=9.2 Hz,1H), 4.15 (s, 2H), 4.07 (t, J=8.8 Hz, 0.5H), 3.93 (t, J=8.8 Hz, 0.5H),3.62-3.73 (m, 3H), 2.23 (s, 3H), 1.33 (d, J=6.0 Hz, 3H). MS (ES) m/z:425 [M+Na]⁺.

Synthesis Example 5: Compound #20(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methylphenyl)-5-fluoro-6-(fluoromethyl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of(2S,3R,4S,5R,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol(28.9 g, 131.23 mmol, 1.00 equiv) in pyridine (450 mL) was added benzylchloride (58.9 g, 419.01 mmol, 3.20 equiv) dropwise at −30° C. Thereaction was stirred for 7 h at 25° C. Ice water was added and themixture was extracted with ethyl acetate thrice. The combined extractswere washed with 1N HCl, brine and dried over Na₂SO₄. The mixture wasthen concentrated and purified by chromatography on silica gel (2:1PE/EA) to yield(2S,3R,4S,5S,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-hydroxytetrahydro-2H-pyran-3,4-diyldibenzoate as a colorless oil. MS (ES) m/z: 555 [M+Na]⁺.

To a mixture of(2S,3R,4S,5S,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-hydroxytetrahydro-2H-pyran-3,4-diyldibenzoate (29.5 g, 55.40 mmol, 1.00 equiv) in dichloromethane (400 mL)was added DAST [(diethylamino)sulfur trifluoride] (24.5 g, 110.86 mmol,2.00 equiv) dropwise at −30° C. The reaction was stirred for 3.5 h atroom temperature. NaHCO₃/H₂O was added and the mixture was extractedwith DCM thrice. The combined extracts were washed with brine and driedover Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield(2S,3R,4R,5R,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diyldibenzoate as a light yellow oil. MS (ES) m/z: 557 [M+Na]⁺.

To a mixture of(2S,3R,4R,5R,6R)-2-(allyloxy)-6-((benzoyloxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diyldibenzoate (21 g, 39.29 mmol, 1.00 equiv) in methanol (300 mL) was addedMeONa (212 mg, 3.929 mmol, 0.1 equiv). The reaction was stirred forovernight at room temperature. Amberlight IR-120 (H⁺) was added and themixture was filtered. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a light yellow oil. MS (ES) m/z: 245 [M+Na]⁺.

To a mixture of(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(12 g, 54.00 mmol, 1.00 equiv) in DMF (200 mL) with imidazole (11 g,161.58 mmol, 3.00 equiv) was added TBDPSCl (tert-butyldiphenylsilylchloride) (22.2 g, 1.50 equiv). The reaction was stirred for 3 h at 20°C. Ice water was added and the mixture was extracted with EA thrice. Thecombined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (1:1 PE/EA) to yield(2S,3R,4R,5S,6R)-2-(allyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diolas a colorless oil.

To a mixture of(2S,3R,4R,5S,6R)-2-(allyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-3,4-diol(6.2 g, 13.46 mmol, 1.00 equiv) in DMF (60 mL) with BnBr (benzylbromide) (9.2 g, 53.79 mmol, 4.00 equiv) was added sodium hydride (1.3g, 54.17 mmol, 4.00 equiv, 60% purity) at 0° C. The reaction was stirredfor 10 h at room temperature. Ice water was added and the mixture wasextracted with EA thrice. The combined extracts were washed with brineand dried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (20:1 PE/EA) to yield(((2R,3R,4R,5R,6S)-6-(allyloxy)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)diphenylsilaneas a yellow oil. MS (ES) m/z: 663 [M+Na]⁺.

To a mixture of(((2R,3R,4R,5R,6S)-6-(allyloxy)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)diphenylsilane(5.8 g, 9.05 mmol, 1.00 equiv) in THF (60 mL) with ZnCl₂ (3 g, 22.01mmol, 2.50 equiv) and Bu₃SnH (10.5 g, 4.00 equiv) was added Pd(PPh₃)₄(2.6 g, 2.25 mmol, 0.25 equiv). The reaction was stirred for 3 h at roomtemperature. Ice water was added and the mixture was extracted with EAthrice. The combined extracts were washed with brine and dried overNa₂SO₄. The mixture was then concentrated and purified by chromatographyon silica gel (4:1 PE/EA) to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil. MS (ES) m/z: 623 [M+Na]⁺.

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(4.62 g, 7.70 mmol, 1.00 equiv) in DMSO (100 mL) was added aceticanhydride (50 mL) at room temperature. The reaction was stirred for 5 hat room temperature. Ice water was added and the mixture was extractedwith EA thrice. The combined extracts were washed with H₂O, brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (4:1 PE/EA) to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-oneas a yellow oil. MS (ES) m/z: 621 [M+Na]⁺.

To a mixture of2-(4-(benzyloxy)-5-bromo-2-methylbenzyl)benzo[b]thiophene (780 mg, 1.84mmol, 1.10 equiv) in THF (15 mL) was added n-BuLi (2.5 M in hexane, 0.74mL, 1.10 equiv) dropwise at −78° C. The reaction was stirred for 30 minat −78° C. To the mixture was then added a solution of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one(1 g, 1.67 mmol, 1.00 equiv) in THF (10 mL) dropwise at −78° C. Thereaction was stirred for 2 h at −78° C. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (20:1 PE/EA)to yield(3R,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil.

To a mixture of(3R,4R,5R,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(700 mg, 0.74 mmol, 1.00 equiv) in DCM/CH₃CN (5/5 mL) with Et₃SiH (260mg, 2.24 mmol, 3.00 equiv) was added BF₃.Et₂O (289 mg, 2.22 mmol, 3.00equiv) dropwise at 0° C. The reaction was stirred for 1 h at 0° C.Sodium bicarbonate was added and the mixture was extracted with DCMthrice. The combined extracts were washed with brine and dried overNa₂SO₄. The mixture was then concentrated and purified by chromatographyon silica gel (10:1 PE/EA) to yield((2R,3R,4R,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methanolas a colorless oil.

To a mixture of((2R,3R,4R,5S,6S)-6-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-4,5-bis(benzyloxy)-3-fluorotetrahydro-2H-pyran-2-yl)methanol(70 mg, 0.100 mmol, 1.00 equiv) in dichloromethane (5 mL) was added DAST(50 mg, 0.310 mmol, 3.00 equiv) dropwise at −20° C. The reaction wasstirred at room temperature for 3 h. Sodium bicarbonate was added andthe mixture was extracted with DCM twice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (5:1 PE/EA) toyield(2S,3S,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-(fluoromethyl)tetrahydro-2H-pyranas a yellow oil. MS (ES) m/z: 713 [M+Na]⁺.

To a mixture of(2S,3S,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-(benzyloxy)-4-methylphenyl)-3,4-bis(benzyloxy)-5-fluoro-6-(fluoromethyl)tetrahydro-2H-pyran(20 mg, 0.030 mmol, 1.00 equiv) in dichloromethane (2 mL) with1,2,3,4,5-pentamethylbenzene (40 mg, 0.270 mmol, 9.32 equiv) was addedBCl₃ (0.4 mL, 0.400 mmol, 13.3 equiv) dropwise at −78° C. The reactionwas stirred for 1 h at −78° C. Methanol was added. The resulting mixturewas concentrated and purified by Pre-HPLC (33%-48% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(5-(benzo[b]thiophen-2-ylmethyl)-2-hydroxy-4-methylphenyl)-5-fluoro-6-(fluoromethyl)tetrahydro-2H-pyran-3,4-diol as a whitesolid.

¹H NMR (400 MHz, CD₃OD) δ: 7.73 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.0 Hz,1H), 7.20-7.29 (m, 3H), 6.92 (s, 1H), 6.70 (s, 1H), 4.61-4.70 (m, 3H),4.45 (t, J=9.6 Hz, 0.5H), 4.33 (t, J=9.6 Hz, 0.5H), 4.17 (s, 2H),3.76-3.85 (m, 2H), 3.64 (t, J=9.2 Hz, 1H), 2.23 (s, 3H). MS (ES) m/z:443 [M+Na]⁺.

Synthesis Example 6: Compound #922-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile

To a mixture of2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(110 mg, 0.16 mmol, 1.00 equiv) in methanol (3 mL) with potassiumcarbonate (69.3 mg, 0.50 mmol, 3.10 equiv) was added BrCN (cyanogenbromide) (86 mg, 0.81 mmol, 5.00 equiv), and the reaction was stirredfor 4 h at 20° C. Water was added and the mixture was extracted with EAthrice. The combined extracts were washed with brine and dried overNa₂SO₄. The mixture was then concentrated and purified by chromatographyon silica gel (30:1 PE/EA) to yield2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrileas a light brown oil. MS (ES) m/z: 703.3[M+H]⁺

To a mixture of2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile(65 mg, 0.09 mmol, 1.00 equiv) in dichloromethane (3 mL) with1,2,3,4,5-pentamethylbenzene (130 mg, 0.88 mmol, 9.50 equiv) was addedBCl₃ (1.3 mL, 1.30 mmol, 14.10 equiv, 1 M in DCM) at −78° C. Thereaction was stirred at −78° C. for 1 h. Methanol (2 mL) was added. Themixture was then concentrated and purified by chromatography onPrep-HPLC (0%-45% CH₃CN/H₂O) to yield2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrilesas a white solid.

1H NMR (300 MHz, Methanol-d4) δ: 7.20-7.31 (m, 2H), 7.15 (d, J=7.7 Hz,1H), 6.41 (s, 1H), 4.45 (t, J=9.3 Hz, 0.5H), 4.28 (t, J=9.3 Hz, 0.5H),4.25 (s, 2H), 4.14 (d, J=9.5 Hz, 1H), 4.08 (s, 2H), 3.78-3.91 (m, 1H),3.68-3.78 (m, 2H), 3.35-3.64 (m, 4H), 2.88 (t, J=5.6 Hz, 2H), 2.27 (s,3H). MS (ES) m/z: 431.0[M−H]⁻.

Synthesis Example 7: Compound #1032-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile

To a mixture of1-(benzyloxy)-2-bromo-4-(dimethoxymethyl)-5-methylbenzene (856 mg, 2.44mmol, 1.10 equiv) in tetrahydrofuran (25 mL) was added n-BuLi (2.5M inhexane, 1.06 mL, 2.66 mmol, 1.20 equiv) dropwise at −78° C., the mixturewas stirred for 30 mins at −78° C. After that,(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-(benzyloxymethyl)-5-fluoro-tetrahydropyran-2-one(1 g, 2.22 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) was added. Thereaction was stirred at −78° C. for 2 h. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-2-(2-(benzyloxy)-5-(dimethoxymethyl)-4-methylphenyl)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil.

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-2-(2-(benzyloxy)-5-(dimethoxymethyl)-4-methylphenyl)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(1.8 g, 2.49 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) was added HCl(1 N, 30 mL). The reaction was stirred at room temperature for 2 h. Themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (4:1 PE/EA) toyield4-(benzyloxy)-5-((3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylbenzaldehydeas a yellow oil. MS (ES) m/z: 694.2[M+NH₄]⁺

To a mixture of tert-butyl2-bromo-4H,5H,6H,7H-thieno[3,2-c]pyridine-5-carboxylate (1.62 g, 5.09mmol, 3.00 equiv) in tetrahydrofuran (16 mL) was added n-BuLi (2.5M inhexane, 2.03 mL, 5.09 mmol, 3.00 equiv) dropwise at −78° C., and themixture was stirred for 25 mins at −78° C.4-(Benzyloxy)-5-((3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylbenzaldehyde(1.15 g, 1.70 mmol, 1.00 equiv) in tetrahydrofuran (4 mL) was then addedto the solution. The reaction was stirred for 2 h at −78° C. NH₄Cl/H₂Owas added and the mixture was extracted with EtOAc thrice. The combinedextracts were washed with brine and dried over Na₂SO₄. The mixture wasthen concentrated and purified by chromatography on silica gel (3:1PE/EA) to yield tert-butyl2-((4-(benzyloxy)-5-((3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylphenyl)(hydroxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylateas a yellow oil.

To a mixture of tert-butyl2-((4-(benzyloxy)-5-((3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylphenyl)(hydroxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(1.25 g, 1.36 mmol, 1.00 equiv) in dichloromethane (12 mL) with Et₃SiH(634 mg, 5.45 mmol, 4.00 equiv) was added BF₃.Et₂O (775 mg, 5.45 mmol,4.00 equiv) dropwise at 0° C. The reaction was stirred at 0° C. for 1 h.Sodium bicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (11:1 DCM/MeOH) to yield2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridineas a yellow oil.

To a mixture2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(150 mg, 0.19 mmol, 1.00 equiv) in MeOH (5 mL) with K₂CO₃ (79.5 mg, 0.58mmol, 3.00 equiv) was added BrCN (101 mg, 0.95 mmol, 5.00 equiv). Thereaction was stirred at room temperature for 4 h. Water (0.1 mL) wasadded to quench the reaction. The mixture was then concentrated andpurified by chromatography on silica gel (78:22 PE/EtOAc) to yield2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrileas a yellow oil.

To a mixture of2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile(130 mg, 0.16 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (238 mg, 1.61 mmol, 10.00 equiv) was addedBCl₃ (1M in DCM, 2.60 mL, 2.60 mmol, 16.20 equiv) dropwise at −78° C.The reaction was stirred for 30 min at −78° C. Methanol (3 mL) was addedto quench the reaction. The mixture was then concentrated and purifiedby chromatography on a C18 reversed column ACN/H₂O (5%-40%) to yield2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.17 (s, 1H), 6.65 (s, 1H), 6.38 (s, 1H),4.56 (d, J=9.7 Hz, 1H), 4.46 (t, J=9.3 Hz, 0.5H), 4.29 (t, J=9.3 Hz,0.5H), 4.25 (s, 2H), 3.99 (s, 2H), 3.69-3.86 (m, 3H), 3.56-3.64 (m, 2H),3.49 (t, J=5.7 Hz, 2H), 2.87 (t, J=5.8 Hz, 2H), 2.18 (s, 3H); MS (ES)m/z: 447.1[M−H]⁻

Synthesis Example 8: Compound #1102-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-4-methoxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile

To a mixture of2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrile,prepared as in Synthesis Example 7 above (20 mg, 0.04 mmol, 1.00 equiv)in N,N-dimethylformamide (1.5 mL) with K₂CO₃ (18.5 mg, 0.13 mmol, 3.00equiv) was added CH₃1 (25.3 mg, 0.17 mmol, 4.00 equiv). The reaction wasstirred at room temperature for 2 h. The resulting mixture was purifiedby chromatography on a C18 reversed column ACN/H₂O (5%-40%) to yield2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-methoxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carbonitrileas a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.14 (s, 1H), 6.70 (s, 1H), 6.28 (s, 1H),4.57 (d, J=9.8 Hz, 1H), 4.30 (t, J=9.3 Hz, 0.5H), 4.17 (t, J=9.3 Hz,0.5H), 4.14 (s, 2H), 3.92 (s, 2H), 3.56-3.74 (m, 6H), 3.43-3.51 (m, 2H),3.39 (t, J=5.7 Hz, 2H), 2.77 (t, J=5.8 Hz, 2H), 2.17 (s, 3H); MS (ES)m/z: 461.1[M−H]⁻

Synthesis Example 9: Compound #86Cyclopentyl(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanone

To a mixture of2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(110 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (5 mL) withtriethylamine (71 mg, 0.70 mmol, 5.00 equiv) was addedcyclopentanecarbonyl chloride (47 mg, 0.35 mmol, 2.53 equiv) dropwise at0° C. The reaction was stirred at room temperature for 2 h. The mixturewas then concentrated and purified by chromatography on silica gel (1:1PE/EA) to yield(2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(cyclopentyl)methanoneas a light yellow oil.

To a mixture of(2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(cyclopentyl)methanone(85 mg, 0.10 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (170 mg, 1.15 mmol, 11.87 equiv) was addedBCl₃ (1.7 mL, 1.70 mmol, 17.58 equiv) dropwise at −78° C. The reactionwas stirred for 1 h at −78° C. Methanol was added. The mixture was thenconcentrated and purified by chromatography on C18 (5%-40% CH₃CN/H₂O) toyieldcyclopentyl(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methanoneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.17 (s, 1H), 6.65 (s, 1H), 6.41 (d, J=5.1Hz, 1H), 4.50-4.59 (m, 3H), 4.46 (t, J=9.0 Hz, 0.5H), 4.29 (t, J=9.0 Hz,0.5H), 3.99 (s, 2H), 3.83-3.87 (m, 3H), 3.71-3.79 (m, 2H), 3.55-3.65 (m,2H), 3.04-3.14 (m, 1H), 2.73-2.82 (m, 2H), 2.19 (s, 3H), 1.58-1.96 (m,8H); MS (ES) m/z: 520.1 [M+H]⁺.

Synthesis Example 10: Compound #84(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-y)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanone

To a mixture of2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(100 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (3 mL) withtriethylamine (52 mg, 0.51 mmol, 4.03 equiv) was added1,3-thiazole-2-carbonyl chloride (37.5 mg, 0.25 mmol, 1.99 equiv)dropwise at 0° C. The reaction was stirred for 2 h at room temperature.The mixture was then concentrated and purified by chromatography onsilica gel (1:1 PE/EA) to yield(2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanoneas a light yellow oil.

To a mixture of(2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanone(25 mg, 0.03 mmol, 1.00 equiv) in dichloromethane (3 mL) with1,2,3,4,5-pentamethylbenzene (50 mg, 0.34 mmol, 12.08 equiv) was addedBCl₃ (0.5 mL, 0.50 mmol, 17.88 equiv) dropwise at −78° C. The reactionwas stirred for 1 h at −78° C. Methanol was added. The mixture was thenconcentrated and purified by chromatography on C18 (5%-40% CH₃CN/H₂O) toyield(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanoneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.98 (s, 1H), 7.83 (s, 1H), 7.20 (s, 1H),6.66 (s, 1H), 6.42 (d, J=26.1 Hz, 1H), 5.27 (s, 1H), 4.68 (s, 1H),4.46-4.60 (m, 3H), 4.46 (t, J=9.0 Hz, 0.5H), 4.29 (t, J=9.9 Hz, 0.5H),3.99-4.07 (m, 2H), 3.68-3.78 (m, 3H), 3.54-3.66 (m, 2H), 2.85-2.94 (m,2H), 2.20 (s, 3H); MS (ES) m/z: 535.1 [M+H]⁺.

Synthesis Example 11: Compound #66(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(pyrrolidin-1-yl)methanone

To a mixture of2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(90 mg, 0.11 mmol, 1.00 equiv) in dichloromethane (3 mL) withtriethylamine (34.8 mg, 0.34 mmol, 3.00 equiv) was addedpyrrolidine-1-carbonyl chloride (23 mg, 0.17 mmol, 1.50 equiv) dropwiseat 0° C. The reaction was stirred for 2 h at room temperature. Themixture was then concentrated and purified by chromatography on silicagel (1:1 PE/EA) to yield(2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(pyrrolidin-1-yl)methanoneas a colorless oil. MS (ES) m/z: 881.4 [M+H]⁺.

To a mixture of(2-(4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(pyrrolidin-1-yl)methanone(60 mg, 0.07 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (120 mg, 0.81 mmol, 11.89 equiv) was addedBCl₃ (1.2 mL, 1.20 mmol, 17.6 equiv) dropwise at −78° C. The reactionwas stirred for 1 h at −78° C. Methanol was added. The mixture was thenconcentrated and purified by chromatography on C18 (½ CH₃CN/H₂O) toyield(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(pyrrolidin-1-yl)methanoneas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.17 (s, 1H), 6.65 (s, 1H), 6.36 (s, 1H),4.58 (d, J=9.6 Hz, 1H), 4.46 (t, J=9.2 Hz, 0.5H), 4.29 (t, J=9.2 Hz,0.5H), 4.24 (s, 2H), 3.96 (s, 2H), 3.65-3.87 (m, 3H), 3.53-3.62 (m, 4H),3.38-3.42 (m, 4H), 2.80 (t, J=5.3 Hz, 2H), 2.20 (s, 3H), 1.83-1.86 (m,4H); MS (ES) m/z: 521.1 [M+H]⁺.

Synthesis Example 12: Compound #109(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanone

To a mixture of 2-bromo-4H,5H,6H,7H-thieno[3,2-c]pyridine-5-carboxylate(2.0 g, 6.28 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) was addedn-BuLi (2.64 mL, 6.60 mmol, 1.05 equiv, 2.5 M in hexane) dropwise at−78° C. The reaction was stirred for 20 min at −78° C. Then the solutionof 5-bromo-2-methylbenzaldehyde (1.38 g, 6.93 mmol, 1.10 equiv) in THF(1.0 mL) was added at −78° C. The reaction was stirred at −78° C. for 2h. NH₄Cl/H₂O was added and the mixture was extracted with EtOAc thrice.The combined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (80:1 PE/EA) to yield tert-butyl2-((5-bromo-2-methylphenyl)(hydroxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylateas a light yellow solid.

To a mixture of tert-butyl2-((5-bromo-2-methylphenyl)(hydroxy)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(2.56 g, 5.84 mmol, 1.00 equiv) and triethylsilane (1.36 g, 11.70 mmol,2.00 equiv) in dichloromethane (60 mL) was added trifluoroacetic acid(1.0 g, 8.77 mmol, 1.50 equiv) at 0° C., and the reaction mixturestirred for 3 h at 0° C. Sodium bicarbonate was added and the mixturewas extracted with DCM thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (20:1 PE/EA) gave 800 mg (32%)of tert-butyl2-(5-bromo-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylateas a light yellow solid. MS (ES) m/z: 422.0 [M+H]⁺.

To a mixture of tert-butyl2-(5-bromo-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(420 mg, 0.99 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was addeddropwise n-BuLi (0.44 mL, 1.10 mmol, 1.10 equiv, 2.5 M in hexane) at−78° C. The mixture was stirred for 20 min at the same temperature. Thena solution of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(493 mg, 1.09 mmol, 1.10 equiv) in THF (1.5 mL) was added dropwise at−78° C. The reaction was stirred at −78° C. for 2 h, NH₄Cl/H₂O was addedand the mixture was extracted with EtOAc thrice. The combined extractswere washed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (30:1 PE/EA)gave 703 mg (89%) of tert-butyl2-(5-((3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylateas a light brown oil.

To a mixture of tert-butyl2-(5-((3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluoro-2-hydroxytetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate(703 mg, 0.89 mmol, 1.00 equiv) and Et₃SiH (513.5 mg, 4.42 mmol, 5.00equiv) in dichloromethane (20 mL) was added BF₃.Et₂O (628.6 mg, 5.00equiv) dropwise at 0° C. The reaction was stirred for 3 h at 0° C.Sodium bicarbonate was added and the mixture was extracted with DCMthrice. The combined extracts were washed with brine and dried overNa₂SO₄. The mixture was then concentrated and purified by chromatographyon silica gel (3:1 PE/EA) gave 300 mg (50%) of2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridineas a light brown oil. MS (ES) m/z: 678.3 [M+H]⁺.

To a mixture of2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(70 mg, 0.10 mmol, 1.00 equiv) in tetrahydrofuran (1.5 mL) with pyridine(24.5 mg, 0.31 mmol, 3.00 equiv) was added 1,3-thiazole-2-carbonylchloride (30.5 mg, 0.21 mmol, 2.00 equiv) at 0° C. The reaction wasstirred for 3 h at 25° C. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (20:1 PE/EA) gave 60 mg (74%)of(2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanoneas a light brown oil. MS (ES) m/z: 830.2 [M+H+ACN]⁺.

To a mixture of(2-(5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanone(70 mg, 0.09 mmol, 1.00 equiv) and 1,2,3,4,5-pentamethylbenzene (140 mg,0.94 mmol, 10.60 equiv) in dichloromethane (3 mL) was added BCl₃ (1 M inDCM, 1.4 mL, 1.40 mmol, 15.70 equiv) dropwise at −78° C. The reactionwas stirred for 50 min at −78° C. Methanol was added. The mixture wasthen concentrated and purified by chromatography on C18 column (MeCN/H₂O40:60) to yield(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanoneas a white solid.

¹H NMR (400 MHz, Methanol-d4) δ: 7.87 (d, J=3.2 Hz, 1H), 7.73 (t, J=3.5Hz, 1H), 7.09-7.21 (m, 2H), 7.04 (dd, J=8.2, 3.5 Hz, 1H), 6.34 (d,J=37.0 Hz, 1H), 5.17 (s, 1H), 4.58 (s, 1H), 4.41 (t, J=5.7 Hz, 1H), 4.32(t, J=9.6 Hz, 0.5H), 4.17 (t, J=9.6 Hz, 0.5H), 3.90-4.10 (m, 4H), 3.74(d, J=12.2 Hz, 1H), 3.44-3.69 (m, 3H), 3.31 (dd, J=10.7, 8.0 Hz, 1H),2.75-2.88 (m, 2H), 2.17 (d, J=7.6 Hz, 3H). MS (ES) m/z: 519.1 [M+H]⁺.

Synthesis Example 13: Compound #112(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-4-methoxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanone

To a mixture of(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanone,prepared as in Synthesis Example 12 above (10 mg, 0.02 mmol, 1.00 equiv)in N,N-dimethylformamide (1.5 mL) with K₂CO₃ (7.8 mg, 0.06 mmol, 3.00equiv) was added CH₃1 (10.6 mg, 0.07 mmol, 4.00 equiv). The reactionmixture was stirred at room temperature for 2 h. The resulting mixturewas then purified by chromatography on a C18 reversed column (ACN/H₂O40:60) to yield(2-(5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-methoxy-2-methylbenzyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)(thiazol-2-yl)methanoneas a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.96 (d, J=3.2 Hz, 1H), 7.82 (d, J=3.5 Hz,1H), 7.24 (d, J=7.7 Hz, 1H), 6.80 (s, 1H), 6.40 (d, J=35.7 Hz, 1H), 5.25(s, 1H), 4.67 (d, J=7.0 Hz, 2H), 4.50 (t, J=5.7 Hz, 1H), 4.40 (t, J=10.3Hz, 0.5H), 4.26 (t, J=10.3 Hz, 0.5H), 4.02 (s, 3H), 3.80 (s, 4H),3.63-3.79 (m, 2H), 3.58 (d, J=17.5 Hz, 2H), 2.89 (d, J=18.9 Hz, 2H),2.26 (d, J=7.5 Hz, 3H); MS (ES) m/z: 547.0[M−H]⁻

Synthesis Example 14: Compound #61(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

Step 1: 5-Bromo-2,3-dihydrobenzofuran-4-ol

2,3-dihydrobenzofuran-4-ol (3000 mg, 20.93 mmol) was dissolved inmethanol (100 mL), then cooled to −40° C. To the mixture was then addedpyridine tribromide in portions (7.44 g, 20.9 mmol). The resultingmixture was stirred at −40° C. for ½ h, then warmed to room temperatureand stirred at room temperature for 16 h. The solvent was removed underreduced pressure. The residue was partitioned between EtOAc and 1N HClaqueous solution. The combined EtOAc extracts were dried over Na₂SO₄,filtered, concentrated. The residue was purified by flash columnchromatography on silica gel (80 g, EtOAc/heptane: 0>>>10%) to yield5-bromo-2,3-dihydrobenzofuran-4-ol as a white solid. ¹H NMR(CHLOROFORM-d) δ: 7.17 (d, J=8.6 Hz, 1H), 6.32 (d, J=8.6 Hz, 1H),5.48-5.63 (m, 1H), 4.61 (t, J=8.8 Hz, 2H), 3.21 (t, J=8.8 Hz, 2H).

Step 2: 5-Bromo-7-iodo-2,3-dihydrobenzofuran-4-ol

To 5-bromo-2,3-dihydrobenzofuran-4-ol (689 mg, 3.20 mmol) in 30 ml ofacetonitrile was added NIS (N-iodosuccinimide) (757 mg, 3.36 mmol) andthe reaction mixture was stirred at room temperature for 2 h. Themixture was concentrated and the residue was purified by flash columnchromatography on silica gel (EtOAc/heptane: 0>>>5%>>>20%) to yield5-bromo-7-iodo-2,3-dihydrobenzofuran-4-ol as a white solid. ¹H NMR(CHLOROFORM-d) δ: 7.51 (s, 1H), 5.52 (s, 1H), 4.70 (t, J=8.8 Hz, 2H),3.34 (t, J=8.8 Hz, 2H).

Step 3: 4-(Benzyloxy)-5-bromo-7-iodo-2,3-dihydrobenzofuran

A 250 ml round bottom flask was charged with5-bromo-7-iodo-2,3-dihydrobenzofuran-4-ol (1.10 g, 3.23 mmol) and K₂CO₃.To the mixture was then added acetone (30 mL). The resulting mixture wasstirred at room temperature for 5 min, then benzyl bromide (0.46 ml,3.87 mmol) was added and the resulting mixture was stirred at 50° C. for3 h. The solvent was removed under reduced pressure and the residue waspurified by flash column chromatography on silica gel (EtOAc/heptane:0>>>10%) to yield 4-(benzyloxy)-5-bromo-7-iodo-2,3-dihydrobenzofuran asa white solid. ¹H NMR (CHLOROFORM-d) δ: 7.65 (s, 1H), 7.33-7.47 (m, 5H),5.04 (s, 2H), 4.58 (t, J=8.6 Hz, 2H), 3.18 (t, J=8.8 Hz, 2H). LC/MS: m/z(M+Na)⁺452.9.

Step 4:(4-(Benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol

To a solution of 4-(benzyloxy)-5-bromo-7-iodo-2,3-dihydrobenzofuran(1.40 g, 3.25 mmol) in anhydrous THF (4 mL) was added i-PrMgCl.LiCl(2.50 ml, 1.3 M) at −78° C. under argon and the resulting mixture wasstirred at −40° C. for 40 min. Then a pre-cooled solution of2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (559.8 mg, 3.41 mmol) inTHF (3 ml) was added to the above mixture dropwise, and the resultingmixture was stirred at −78° C. for 1 h. The resulting mixture wasquenched with aqueous NH₄Cl solution, extracted with EtOAc three times.The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel (EtOAc/heptane: 0>>>10%>>>40%) to yield(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanolas a white solid. ¹H NMR (CHLOROFORM-d) δ: 7.43-7.48 (m, 2H), 7.31-7.41(m, 3H), 7.29 (s, 1H), 6.77-6.96 (m, 3H), 5.76 (d, J=4.5 Hz, 1H), 5.02(s, 2H), 4.53 (t, J=8.8 Hz, 2H), 4.23 (s, 4H), 3.07 (t, J=8.6 Hz, 2H),2.68 (d, J=5.1 Hz, 1H). LC/MS: m/z (MH⁺-18): 451.0.

Step 5:6-((4-(Benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine

A 100 ml round bottom flask was charged with(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol(1.07 g, 2.28 mmol) and DCM (30 mL) was added. To the mixture was addedtriethylsilane (1.09 ml, 6.84 mmol) at 0° C., followed by the additionof BF₃.Et₂O (0.43 ml, 3.42 mmol)). The reaction mixture was keptstirring at 0° C. for ½ h. Saturated aqueous NaHCO₃ was added and themixture was stirred at 0° C. for 20 min, and concentrated. The residuewas extracted with dichloromethane three times and the combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel (EtOAc/heptane: 0>>>20%) to yield6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxineas colorless syrup. ¹H NMR (CHLOROFORM-d) δ: 7.43-7.50 (m, 2H),7.30-7.42 (m, 3H), 7.07 (s, 1H), 6.76-6.82 (m, 1H), 6.66-6.73 (m, 2H),5.00 (s, 2H), 4.52 (t, J=8.6 Hz, 2H), 4.23 (s, 4H), 3.72 (s, 2H), 3.10(t, J=8.6 Hz, 2H). LC/MS: m/z (M+Na)⁺: 475.05.

Step 6:(3R,4R,5R,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol

A 25 ml round bottom flask was charged with6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine(291.6 mg, 0.64 mmol) and evacuated, re-filled with argon, and thisprocess was repeated twice. To the mixture was then added anhydrous THF(2 mL) and the solution was cooled to −78° C. n-BuLi (0.4 ml, 1.6 M inhexanes) was added to the resulting solution and the resulting lightorange mixture was stirred at −78° C. for 30 min, then transferred to acooled solution of(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one(336.4 mg, 0.64 mmol) in THF (3 ml) under argon (at −78° C.) viacannula. The reaction mixture was stirred at −78° C. for 1.5 h, quenchedwith aq. NH₄Cl, extracted with EtOAc three times. The combined organiclayer was washed with brine, dried with Na₂SO₄. The inorganic salt wasfiltered off and the filtrate was concentrated under reduced pressure toyield(3R,4R,5R,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol,which was used for the next step reaction without further purification.LC/MS m/z (M+Na)⁺: 919.3.

Step 7:(2S,3R,4R,5S,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

Et₃SiH (0.34 ml, 2.12 mmol) was added in one portion to a stirredsolution of(3R,4R,5R,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(577 mg, 0.64 mmol) in dry DCM (5 ml)/ACN (5 ml) at 0° C. under anatmosphere of argon. After 3 min, BF₃.Et₂O (95 μL) was added dropwise tothe above solution by syringe. The resulting mixture was stirred at −4°C. (in a diluted brine-ice bath) for 15 min, then another portion ofBF₃.Et₂O (95 μL) was added and the mixture was stirred at −4° C. for 25min, quenched with saturated NaHCO₃ (10 ml). The volatile organicsolvent was evaporated under reduced pressure and the residue wasextracted with EtOAc three times. The combined extracts were washed withbrine, dried with Na₂SO₄, and concentrated under vacuum to yield a whitefoam, which was purified by flash column chromatography on silica gel(12 g, EtOAc/heptane: 0>>>10%>>>90%) to yield(2S,3R,4R,5S,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid. ¹H NMR (METHANOL-d₄) δ: 7.47 (d, J=7.1 Hz, 2H),7.24-7.42 (m, 3H), 7.01 (s, 1H), 6.62-6.72 (m, 3H), 5.03-5.11 (m, 1H),4.96-5.02 (m, 1H), 4.48-4.59 (m, 3H), 4.14-4.37 (m, 5H), 3.58-3.77 (m,6H), 3.40-3.49 (m, 1H), 3.22 (t, J=8.8 Hz, 2H).

Step 8:(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

(2S,3R,4R,5S,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(70 mg, 0.13 mmol) was dissolved in EtOAc (8 mL). To the resultingmixture was then added 30% HCl (15 μL) and 20% Pd(OH)₂ (70 mg) and thehydrogen bottle was evacuated, re-filled with hydrogen (43 psi), andthis process was repeated twice. The mixture was shaken with Parrhydrogenation shaker for 2 h. The catalyst was filtered off and thesolvent was evaporated to yield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (MeOH) δ: 6.88 (s, 1H), 6.60-6.68 (m, 3H), 4.50-4.58 (m, 2H),4.45-4.50 (m, 1H), 4.26-4.44 (m, 1H), 4.16 (s, 4H), 3.66 (d, J=3.5 Hz,5H), 3.55 (s, 2H), 3.13 (t, J=8.6 Hz, 2H). LC/MS: m/z (MH⁺): 449.20.

Synthesis Example 15: Compound #65(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

To a 4 ml vial was added(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol,prepared as described in Synthesis Example 14 (18.7 mg, 0.042 mmol),K₂CO₃ (28.8 mg, 0.21 mmol), acetone (1 mL), followed by MeI (26 pL) andthe vial was sealed with a TFE cap and the mixture was stirred at roomtemperature for 16 h. The solid was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was re-dissolved inMeOH (2 mL) and subjected to Gilson HPLC purification (15 min gradienttime, 10%>>>90% ACN, flow rate: 35 ml/min) to yield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (CD₃CN): 7.01 (s, 1H), 6.76 (d, J=8.59 Hz, 1H), 6.72 (s, 1H),6.71 (d, J=8.59 Hz, 1H), 4.58 (t, J=8.59 Hz, 2H), 4.52 (d, J=9.60 Hz,1H), 4.31 (dt, J=51.03 and 9.09 Hz, 1H), 4.22 (m, 1H), 4.21 (s, 3H),3.81 (s, 3H), 3.67-3.78 (4H), 3.52-3.63 (3H), 3.31 (t, J=8.59 Hz, 2H).LC/MS: m/z (M+NH₄)⁺: 480.1.

Synthesis Example 16: Compound #75(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of 2-(2-hydroxyphenyl)acetic acid (15.0 g, 98.59 mmol, 1.00equiv) in methanol (200 mL) was added nBu₄NBr₃ (47.56 g, 98.67 mmol,1.00 equiv) at 0° C. The reaction was stirred for 16 h at roomtemperature. NH₄Cl/H₂O was added and the mixture was extracted withEtOAc thrice. The combined extracts were washed with brine and driedover Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield methyl2-(5-bromo-2-hydroxyphenyl)acetate as a light yellow solid.

To a mixture of methyl 2-(5-bromo-2-hydroxyphenyl)acetate (5.4 g, 22.03mmol, 1.00 equiv) in CH₃CN (100 mL) was added NIS (4.96 g, 22.04 mmol,1.00 equiv) in portions. The reaction was stirred for 3 h at roomtemperature. NH₄Cl/H₂O was added and the mixture was extracted withEtOAc thrice. The combined extracts were washed with sodium bicarbonateand Na₂SO₃ solution. The mixture was then concentrated and purified bychromatography on silica gel (10:1 PE/EA) to yield methyl2-(5-bromo-2-hydroxy-3-iodophenyl)acetate as an off-white solid.

To a mixture of methyl 2-(5-bromo-2-hydroxy-3-iodophenyl)acetate (5.5 g,14.83 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) with potassiumcarbonate (3.07 g, 22.21 mmol, 1.50 equiv) was added MeI (2.52 g, 1.20equiv) dropwise. The reaction was stirred for 16 h at room temperature.NH₄Cl/H₂O was added and the mixture was extracted with EtOAc thrice. Thecombined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (5:1 PE/EA) to yield methyl2-(5-bromo-3-iodo-2-methoxyphenyl)acetate as a yellow oil.

To a mixture of methyl 2-(5-bromo-3-iodo-2-methoxyphenyl)acetate (5.2 g,13.51 mmol, 1.00 equiv) in acetonitrile (50 mL) with4-acetamidobenzene-1-sulfonyl azide (3.9 g, 16.23 mmol, 1.20 equiv) wasadded DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (16.25 g, 106.91 mmol,1.20 equiv), the reaction was stirred for 16 h at room temperature.NH₄Cl/H₂O was added and the mixture was extracted with EtOAc thrice. Thecombined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (10:1 PE/EA) to yield methyl2-(5-bromo-3-iodo-2-methoxyphenyl)-2-diazoacetate as a yellow oil.

To a mixture of Rh₂—(S-DOSP)₄(tetrakis[(S)-(−)-N-(p-dodecylphenylsulfonyl)prolinato]dirhodium (II))(110 mg, 0.01 equiv) in hexane (50 mL) was added methyl2-(5-bromo-3-iodo-2-methoxyphenyl)-2-diazoacetate (2.4 g, 5.84 mmol,1.00 equiv) in hexane (10 mL) at 0° C. The reaction was stirred for 1 hat room temperature. NH₄Cl/H₂O was added and the mixture was extractedwith EtOAc thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield methyl5-bromo-7-iodo-2,3-dihydrobenzofuran-3-carboxylate as a light yellowsolid.

To a mixture of methyl5-bromo-7-iodo-2,3-dihydrobenzofuran-3-carboxylate (200 mg, 0.52 mmol,1.00 equiv) in THF (3 mL) was added DIBAL (diisobutylaluminium hydride)(25% in hexane) (890 g, 6.26 mol, 3.00 equiv) at 0° C. The reaction wasstirred for 1 h at 0° C. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield(5-bromo-7-iodo-2,3-dihydrobenzofuran-3-yl)methanol as a light yellowoil.

To a mixture of (5-bromo-7-iodo-2,3-dihydrobenzofuran-3-yl)methanol (50mg, 0.14 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) was addedsodium hydride (11.3 mg, 0.47 mmol, 2.00 equiv). The reaction wasstirred for 20 min at room temperature. To the mixture was then addedBnBr (48 mg, 0.28 mmol, 2.00 equiv). The reaction was stirred for 3 h atroom temperature. NH₄Cl/H₂O was added and the mixture was extracted withEtOAc thrice. The combined extracts were washed with brine and driedover Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield3-((benzyloxy)methyl)-5-bromo-7-iodo-2,3-dihydrobenzofuran as a yellowsolid.

To a mixture of3-((benzyloxy)methyl)-5-bromo-7-iodo-2,3-dihydrobenzofuran (444 mg, 1.00mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added iPrMgCl.LiCl (0.77mL) at −78° C. To the resulting mixture was then added a solution of2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (149 mg, 0.91 mmol, 0.91equiv) in tetrahydrofuran (2 mL) dropwise with stirring at −78° C. Theresulting solution was stirred for 2 h at −78° C. NH₄Cl/H₂O was addedand the mixture was extracted with EtOAc thrice. The combined extractswere washed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (5:1 PE/EA) toyield(3-((benzyloxy)methyl)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanolas a colorless oil.

To a mixture of(3-((benzyloxy)methyl)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol(240 mg, 0.50 mmol, 1.00 equiv) in dichloromethane (5 mL) with Et₃SiH(115 mg, 0.99 mmol, 1.99 equiv) was added BF₃.Et₂O (106 mg, 0.75 mmol,1.50 equiv) at 0° C. The reaction was stirred for 2 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (3:1 PE/EA) to yield6-((3-((benzyloxy)methyl)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxineas a colorless oil.

To a mixture of6-((3-((benzyloxy)methyl)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine(190 mg, 0.41 mmol, 1.00 equiv) in tetrahydrofuran (4 mL) was addedn-BuLi (017 mL, 2.5M/L) dropwise with stirring at −78° C. The mixturewas stirred for 30 min.(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(174 mg, 0.39 mmol, 0.95 equiv) in tetrahydrofuran (2 mL) was then addedat −78° C. The reaction was stirred at −78° C. for 2 h. NH₄Cl/H₂O wasadded and the mixture was extracted with EtOAc thrice. The combinedextracts were washed with brine and dried over Na₂SO₄. The mixture wasthen concentrated and purified by chromatography on silica gel (5:1PE/EA) to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((benzyloxy)methyl)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-5-fluorotetrahydro-2H-pyran-2-olas a colorless oil.

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(3-((benzyloxy)methyl)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-5-fluorotetrahydro-2H-pyran-2-ol(210 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (4 mL) with Et₃SiH(58 mg, 0.50 mmol, 1.99 equiv) was added BF₃.OEt₂ (53 mg, 0.37 mmol, 1.5equiv) at 0° C. The reaction was stirred for 2 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (4:1 PE/EA) to yield6-((3-((benzyloxy)methyl)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxineas a colorless oil.

To a mixture of6-((3-((benzyloxy)methyl)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine(100 mg, 0.12 mmol, 1.00 equiv) in methanol (15 mL) was added Palladiumcarbon (80 mg). H₂ was introduced. The reaction was stirred overnight at40° C. The solids were filtered out. The mixture was then concentratedand purified by chromatography on C18 (10%-40% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-(hydroxymethyl)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD₃OD): ¹H NMR (300 MHz, CD₃OD): δ: 7.15 (s, 1H), 6.99(s, 1H), 6.67 (s, 3H), 4.65-4.59 (m, 2H), 4.42-4.48 (m, 1H), 4.43 (t,J=9.3 Hz, 0.5H), 4.26 (t, J=9.3 Hz, 0.5H), 4.17 (s, 4H), 4.08 (d, J=9.6Hz, 1H), 3.80-3.55 (m, 9H), 3.43-3.30 (m, 1H). MS (ES) m/z: 480.05[M+18]⁺

Synthesis Example 17: Compound #107(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of 2,3-dihydrobenzofuran-4-ol (5 g, 36.72 mmol, 1.00 equiv)in MeOH (100 mL) was added pyridine hydrobromide perbromide (12.4 g,36.81 mmol, 1.00 equiv) at −20° C. The reaction was stirred at −20° C.for 2 h. Ice/H₂O was added and the mixture was extracted with EA thrice.The combined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (10:1 PE/EA) to yield 5-bromo-2,3-dihydrobenzofuran-4-ol as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ: 7.18 (d, J=8.4 Hz, 1H), 6.32 (d, J=8.4Hz, 1H), 5.52 (s, 1H), 4.59 (t, J=8.7 Hz, 2H), 3.22 (t, J=8.7 Hz, 2H).

To a mixture of 5-bromo-2,3-dihydrobenzofuran-4-ol (1 g, 4.65 mmol, 1.00equiv) in dichloromethane (30 mL) with dichloro(methoxy)methane (1.06 g,9.22 mmol, 1.98 equiv) was added TiCl₄ (1.32 g, 6.96 mmol, 1.50 equiv)at 0° C. The reaction was stirred for 1 h at room temperature. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (1:1 PE/EA) to yield5-bromo-4-hydroxy-2,3-dihydrobenzofuran-7-carbaldehyde as a pink solid.¹H NMR (300 MHz, DMSO) δ: 11.08 (s, 1 H), 9.85 (s, 1H), 7.62 (s, 1H),4.72 (t, J=9.0 Hz, 2H), 3.18 (t, J=9.0 Hz, 2H).

To a mixture of 5-bromo-4-hydroxy-2,3-dihydrobenzofuran-7-carbaldehyde(700 mg, 2.88 mmol, 1.00 equiv) in dichloromethane (10 mL) with K₂CO₃(799 mg, 5.78 mmol, 2.01 equiv) was added BnBr (541 mg, 3.16 mmol, 1.10equiv). The reaction was stirred for 1 h at room temperature. Water wasadded and the mixture was extracted with EA thrice. The combinedextracts were washed with brine and dried over Na₂SO₄. The mixture wasthen concentrated and purified by chromatography on silica gel (5:1PE/EA) to yield4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-carbaldehyde as a yellowoil. ¹H NMR (300 MHz, DMSO) δ: 9.94 (s, 1H), 9.84 (s, 1H), 7.71 (s, 1H),7.50-7.53 (m, 2H), 7.34-7.45 (m, 3H), 5.37 (s, 2H), 4.73 (t, J=9.0 Hz,2H), 3.51 (t, J=9.0 Hz, 2H).

To a mixture of 6-bromo-2,3-dihydrobenzo[b][1,4]oxathiine (510 mg, 2.21mmol, 1.10 equiv) in THF (10 mL) was added n-BuLi (0.88 mL, 1.10 equiv,2.5M) at −78° C. The solution was stirred for 30 min at −78° C. Afterthat was added a solution of4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-carbaldehyde (666 mg, 2.00mmol, 1.00 equiv) in tetrahydrofuran (2 mL) at −78° C. The reaction wasstirred for at −78° C. 1 h. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (1:1 PE/EA) to yield(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methanolas a yellow oil. MS (ES) m/z: 467 [M-OH]⁺

To a mixture of(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methanol(700 mg, 1.44 mmol, 1.00 equiv) in dichloromethane (10 mL) with Et₃SiH(503 mg, 4.33 mmol, 3.00 equiv) was added CF₃COOH (329 mg, 2.89 mmol,2.00 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiineas a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ: 7.45-7.48 (m, 2H),7.33-7.40 (m, 3H), 7.06 (s, 1H), 6.81-6.87 (m, 2H), 6.74 (d, J=8.1 Hz,1H), 5.01 (s, 2H), 4.52 (t, J=8.7 Hz, 2H), 4.37-4.39 (m, 2H), 3.70 (s,2H), 3.10-3.13 (m, 4H).

To a mixture of6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiine(150 mg, 0.32 mmol, 1.10 equiv) in tetrahydrofuran (2 mL) was addedn-BuLi (0.13 mL, 1.10 equiv, 2.5M) at −78° C. The reaction was stirredfor 30 min at −78° C. To the resulting mixture was then added a solutionof(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(131 mg, 0.29 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) at −78° C. Thereaction was stirred at −78° C. for 1 h. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (1:1 PE/EA) toyield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil. MS (ES) m/z: 823 [M-OH]⁺

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(160 mg, 0.19 mmol, 1.00 equiv) in dichloromethane (1 mL) with Et₃SiH(45 mg, 0.39 mmol, 2.03 equiv) was added BF₃.Et₂O (27 mg, 0.19 mmol,1.00 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiineas a yellow oil. MS (ES) m/z: 826 [M+H]⁺.

To a mixture of6-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiine(100 mg, 0.12 mmol, 1.00 equiv) in dichloromethane (5 mL) with1,2,3,4,5-pentamethylbenzene (100 mg, 0.67 mmol, 5.57 equiv) was addedBCl₃ (2 mL, 1 N, 0.002 mmol, 16.7 equiv) at −78° C. The reaction wasstirred at −78° C. for 1 h. 5 mL of methanol was added. The mixture wasthen concentrated and purified by chromatography on a C18 reversed phasecolumn (0%-45% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid. MS (ES) m/z: 466 [M+H]⁺

To a mixture of(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(10 mg, 0.02 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL) withpotassium carbonate (20 mg, 0.14 mmol, 6.72 equiv) was added CH₃1 (20mg, 0.14 mmol, 6.55 equiv). The reaction was stirred for 1 h at roomtemperature. The solids were filtered out. The mixture was thenconcentrated and purified by chromatography on a C18 reversed phasecolumn (0%-45% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD3OD) δ: 6.99 (s, 1H), 6.80-6.83 (m, 2H), 6.65 (d,J=3.9 Hz, 1H), 4.51-4.57 (m, 3H), 4.23-4.43 (m, 3H), 3.84 (s, 3H),3.55-3.82 (m, 7H), 3.32-3.34 (m, 1H), 3.28-3.30 (m, 1H), 3.09-3.11 (m,2H). MS (ES) m/z: 496.1 [M+NH4]+

Synthesis Example 18: Compound #108(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(4-methoxy-7-((1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(4-methoxy-7-((1,2,3,4-tetrahydroquinolin-7-yl)methyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4-diol,prepared for example, as described in Example 19, below (15 mg, 0.03mmol, 1.00 equiv) in methanol (1 ml) with HCHO (16.3 mg, 0.16 mmol, 4.99equiv) was added acetic acid (0.01 mL) and NaBH₃CN (10 mg, 0.16 mmol,4.87 equiv). The reaction was stirred for 1 h at room temperature. Themixture was then concentrated and purified by chromatography on a C18(0%-45% CH₃CN/H₂O) reversed phase column to yield(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(4-methoxy-7-((1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)methyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.01 (s, 1H), 6.75-6.77 (m, 1H), 6.54 (s,1H), 6.38-6.42 (m, 1H), 4.49-4.59 (m, 3H), 4.30-4.43 (m, 0.5H),4.18-4.30(m, 0.5H), 3.83 (s, 3H), 3.59-3.72 (m, 3H), 3.73-3.78 (m, 7H), 3.27-3.31(m, 2H), 3.16 (t, J=6.0 Hz, 2H), 2.82 (s, 3H), 2.69 (t, J=6.0 Hz, 2H),1.94-1.96 (m, 2H). MS (ES) m/z: 474.2 [M+H]⁺.

Synthesis Example 19: Compound #105(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(4-methoxy-7-((1,2,3,4-tetrahydroquinolin-7-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of 7-bromo-1,2,3,4-tetrahydroquinoline (2 g, 8.05 mmol,1.00 equiv) in N,N-dimethylformamide (20 mL) was added sodium hydride(970 mg, 24.25 mmol, 3.01 equiv) at 0° C. The mixture was stirred for 1h at 0° C. To the resulting mixture was then added 3-bromoprop-1-ene(2.93 g, 24.22 mmol, 3.01 equiv) at 0° C. The reaction was stirredovernight at room temperature. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (100:1 PE/EA) to yield1-allyl-7-bromo-1,2,3,4-tetrahydroquinoline as a colorless oil. ¹H NMR(300 MHz, CDCl₃) b 6.78 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.65(s, 1H), 5.76-5.88 (m, 1H), 5.15-5.22 m, 2H), 3.82-3.85 (m, 2H), 3.27(t, J=5.7 Hz, 2H), 2.67-2.71 (m, 2H), 1.89-1.98 (m, 2H).

To a mixture of 1-allyl-7-bromo-1,2,3,4-tetrahydroquinoline (1.0 g, 3.97mmol, 1.32 equiv) in tetrahydrofuran (10 mL) was added n-BuLi (1.6 mL,1.30 equiv, 2.5M) at −78° C. The reaction was stirred for 30 min at −78°C. To the resulting mixture was then added a solution of4-(benzyloxy)-5-bromo-2,3-dihydro-1-benzofuran-7-carbaldehyde (1.0 g,3.00 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) at −78° C. The reactionwas stirred at −78° C. for 1 h. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (1:1 PE/EA) to yield(1-allyl-1,2,3,4-tetrahydroquinolin-7-yl)(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methanolas a yellow oil. MS (ES) m/z: 507[M+H]⁺

To a mixture of(1-allyl-1,2,3,4-tetrahydroquinolin-7-yl)(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methanol(800 mg, 1.58 mmol, 1.00 equiv) in dichloromethane (10 mL) with Et₃SiH(550 mg, 4.73 mmol, 2.99 equiv) was added CF₃COOH (360 mg, 3.16 mmol,2.00 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield1-allyl-7-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-1,2,3,4-tetrahydroquinolineas a yellow oil. MS (ES) m/z: 491 [M+H]⁺.

To a mixture of1-allyl-7-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-1,2,3,4-tetrahydroquinoline(350 mg, 0.71 mmol, 1.10 equiv) in tetrahydrofuran (3 mL) was addedn-BuLi (0.29 mL, 1.10 equiv, 2.5M) at −78° C. The mixture was stirredfor 30 min at −78° C. To the resulting mixture was then added a solutionof(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(292 mg, 0.65 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) at −78° C. Thereaction was stirred at −78° C. for 1 h. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (1:1 PE/EA) toyield(3R,4R,5R,6R)-2-(7-((1-allyl-1,2,3,4-tetrahydroquinolin-7-yl)methyl)-4-(benzyloxy)-2,3-dihydrobenzofuran-5-yl)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil. MS (ES) m/z: 863[M+H]⁺

To a mixture of(3R,4R,5R,6R)-2-(7-((1-allyl-1,2,3,4-tetrahydroquinolin-7-yl)methyl)-4-(benzyloxy)-2,3-dihydrobenzofuran-5-yl)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-ol(390 mg, 0.45 mmol, 1.00 equiv) in dichloromethane (4 mL) with Et₃SiH(110 mg, 0.95 mmol, 2.09 equiv) was added BE₃.Et₂O (101 mg, 0.71 mmol,1.57 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield1-allyl-7-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1,2,3,4-tetrahydroquinolineas a yellow oil. MS (ES) m/z: 847[M+H]⁺

To a mixture of1-allyl-7-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1,2,3,4-tetrahydroquinoline(220 mg, 0.26 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) with ZnCl₂ (89mg, 0.65 mmol, 2.51 equiv) was added Pd(PPh₃)₄(75 mg, 0.06 mmol, 0.25equiv) and n-Bu₃SnH (305 mg, 1.04 mmol, 4.02 equiv). The reaction wasstirred for 2 h at room temperature. NH₄Cl/H₂O was added and the mixturewas extracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (1:1 PE/EA) to yield7-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1,2,3,4-tetrahydroquinolineas a yellow oil. MS (ES) m/z: 807[M+H]⁺

To a mixture of7-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-1,2,3,4-tetrahydroquinoline(190 mg, 0.24 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) withtriethylamine (120 mg, 1.19 mmol, 5.03 equiv), 4-dimethylaminopyridine(10 mg, 0.08 mmol, 0.35 equiv) was added (Boc)₂O (257 mg, 1.18 mmol,5.00 equiv). The reaction was stirred overnight at 75° C. The mixturewas then concentrated and purified by chromatography on silica gel (5:1PE/EA) to yield tert-butyl7-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-3,4-dihydroquinoline-1(2H)-carboxylateas a yellow oil. MS (ES) m/z: 907[M+H]⁺.

To a mixture of tert-butyl7-((4-(benzyloxy)-5-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-7-yl)methyl)-3,4-dihydroquinoline-1(2H)-carboxylate (120 mg, 0.13 mmol, 1.00 equiv) in MeOH (5 mL) withacetic acid (0.1 mL) was added dry Palladium carbon (120 mg). H₂ (g) wasintroduced. The reaction was stirred overnight at room temperature. Thesolids were filtered out. The resulting mixture was concentrated toyield tert-butyl7-((5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2,3-dihydrobenzofuran-7-yl)methyl)-3,4-dihydroquinoline-1(2H)-carboxylate as a white solid. MS (ES) m/z: 547[M+H]⁺.

To a mixture of tert-butyl7-((5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-hydroxy-2,3-dihydrobenzofuran-7-yl)methyl)-3,4-dihydroquinoline-1(2H)-carboxylate (40 mg, 0.07 mmol, 1.00 equiv) in N,N-dimethylformamide(5 mL) with potassium carbonate (102 mg, 0.74 mmol, 10.07 equiv) wasadded CH₃1 (105 mg, 0.74 mmol, 10.09 equiv). The reaction was stirredfor 2 h at room temperature. The residue was applied chromatograph on aC18 reversed phase column (0%-45% CH₃CN/H₂O) to yield tert-butyl7-((5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)methyl)-3,4-dihydroquinoline-1(2H)-carboxylateas a white solid. MS (ES) m/z: 561 [M+H]⁺.

To a mixture of tert-butyl7-((5-((2S,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)methyl)-3,4-dihydroquinoline-1(2H)-carboxylate (38 mg, 0.07 mmol, 1.00 equiv) in dichloromethane (5mL) was added hydrogen chloride (in diethyl ether) (0.14 mL, 10.00equiv). The reaction was stirred for 1 h at room temperature. Themixture was then concentrated and purified by chromatography on a C18reversed phase column (0%-45% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-(4-methoxy-7-((1,2,3,4-tetrahydroquinolin-7-yl)methyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 6.98 (s, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.45(d, J=7.8 Hz, 1H), 6.30 (s, 1H), 4.53-4.59 (m, 3H), 4.39 (t, J=8.7 Hz,0.5H), 4.22 (t, J=8.7 Hz, 0.5H), 3.78-3.83 (m, 3H), 3.73-3.78 (m, 2H),3.53-3.68 (m, 5H), 3.26-3.33 (m, 2H), 3.17-3.27 (m, 2H), 2.68 (t, J=6.3Hz, 2H), 1.84-1.88 (m, 2H). MS (ES) m/z: 458.1 [M−H]⁻.

Synthesis Example 20: Compound #125(2S,3R,4R,5S,6R)-2-(4-chloro-5-(chroman-6-ylmethyl)-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of 2-(2,6-dichlorophenyl)ethan-1-ol (200 g, 1.05 mol, 1.00equiv) in toluene (3500 mL) was added NaH (52.8 g, 2.20 mol, 1.25 equiv,60% purity). The mixture was stirred for 20 minutes at 40° C. To theresulting solution was then added CuCl (cuprous chloride) (5.21 g, 52.63mmol, 0.05 equiv) and ethyl acetate (4.63 g, 52.61 mmol, 0.05 equiv).The reaction was stirred for overnight at reflux. Ice water was addedand the mixture was extracted with EtOAc thrice. The combined extractswere washed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (50:1 PE/EA)to yield 4-chloro-2,3-dihydrobenzofuran as a yellow oil.

To a mixture of 4-chloro-2,3-dihydrobenzofuran (36 g, 232.87 mmol, 1.00equiv) in AcOH (360 mL) was added Br₂ (37.3 g, 233.40 mmol, 1.00 equiv)dropwise at 10-15° C. The reaction was stirred for 2 h at 10-15° C. Icewater was added, and the solids were collected by filtration to yield5-bromo-4-chloro-2,3-dihydrobenzofuran as a white solid.

To a mixture of 5-bromo-4-chloro-2,3-dihydrobenzofuran (48 g, 205.58mmol, 1.00 equiv) in tetrahydrofuran (1000 mL) was added n-BuLi (2.5M,91 mL) dropwise at −78° C. The mixture was stirred for 20 minutes. Tothe resulting solution was then added DMF (64 ml) dropwise at −78° C.The reaction was stirred at −78° C. for 1 h. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (10:1 PE/EA)to yield 4-chloro-2,3-dihydrobenzofuran-5-carbaldehyde as a yellowsolid.

To a mixture of 4-chloro-2,3-dihydrobenzofuran-5-carbaldehyde (26 g,142.38 mmol, 1.00 equiv) in MeOH (600 mL) was added pyridinehydrobromide perbromide (92 g, 287.50 mmol, 2.00 equiv). The reactionwas stirred for overnight at 25° C. Ice water was added and the mixturewas extracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (10:1 PE/EA) to yield7-bromo-4-chloro-2,3-dihydrobenzofuran-5-carbaldehyde as a white solid.NMR (300 MHz, CDCl₃) δ: 10.25 (s, 1H), 7.98 (s, 1H), 4.88 (t, J=8.9 Hz,2H), 3.39-3.52 (m, 2H). MS (ES) m/z: 261, 263 [M+H]⁺

To a mixture of 6-bromo-3,4-dihydro-2H-1-benzopyran (780 mg, 3.66 mmol,1.20 equiv) in tetrahydrofuran (10 mL) was added n-BuLi (2.5M) (1.59 mL)at −78° C. The mixture was stirred for 30 minutes. To the resultingmixture was then added a solution of7-bromo-4-chloro-2,3-dihydrobenzofuran-5-carbaldehyde (797 mg, 3.05mmol, 1.00 equiv) in tetrahydrofuran (1 mL) at −78° C. The reaction wasstirred at −78° C. for 1 h. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (1:1 PE/EA) to yield(7-bromo-4-chloro-2,3-dihydrobenzofuran-5-yl)(chroman-6-yl)methanol as awhite solid.

To a mixture of(7-bromo-4-chloro-2,3-dihydrobenzofuran-5-yl)(chroman-6-yl)methanol (510mg, 1.29 mmol, 1.00 equiv) in dichloromethane (10 mL) with Et₃SiH (300mg, 2.58 mmol, 2.00 equiv) was added CF₃COOH (221 mg, 1.94 mmol, 1.50equiv) dropwise with stirring at 0° C. The reaction was stirred for 1 hat 0° C. Sodium bicarbonate/H₂O was added and the mixture was extractedwith dichloromethane thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (5:1 PE/EA) to yield6-((7-bromo-4-chloro-2,3-dihydrobenzofuran-5-yl)methyl)chromane as lightyellow oil.

To a mixture of6-((7-bromo-4-chloro-2,3-dihydrobenzofuran-5-yl)methyl)chromane (230 mg,0.61 mmol, 1.10 equiv) in tetrahydrofuran (5 mL) was added n-BuLi (2.5M)(0.27 mL) at −78° C. The mixture was stirred for 30 minutes. To theresulting mixture was then added a solution of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(249 mg, 0.55 mmol, 1.00 equiv) in tetrahydrofuran (0.5 mL) at −78° C.The reaction was stirred at −78° C. for 1 h. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (3:1 PE/EA) toyield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-5-(chroman-6-ylmethyl)-2,3-dihydrobenzofuran-7-yl)-5-fluorotetrahydro-2H-pyran-2-olas a light yellow oil.

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(4-chloro-5-(chroman-6-ylmethyl)-2,3-dihydrobenzofuran-7-yl)-5-fluorotetrahydro-2H-pyran-2-ol(120 mg, 0.16 mmol, 1.00 equiv) in dichloromethane (5 mL) with Et₃SiH(37 mg, 0.32 mmol, 1.99 equiv) was added BF₃.Et₂O (34 mg, 0.24 mmol,1.50 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((7-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-4-chloro-2,3-dihydrobenzofuran-5-yl)methyl)chromaneas a light yellow oil.

To a mixture of6-((7-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-4-chloro-2,3-dihydrobenzofuran-5-yl)methyl)chromane(50 mg, 0.07 mmol, 1.00 equiv) in methanol (5 mL) was added Pd(OH)₂/C(50 mg). H₂ was introduced in. The reaction was stirred for 30 min atroom temperature. The solids were filtered out. The mixture was thenconcentrated and purified by chromatography on a C18 reversed phasecolumn (0%-45% CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(4-chloro-5-(chroman-6-ylmethyl)-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.10 (s, 1H), 6.85 (d, J=9.9 Hz, 2H),6.54-6.64 (m, 1H), 4.50-4.58 (m, 0.5H), 4.31-4.40 (m, 1H), 4.19-4.30 (m,0.5H), 4.08-4.15 (m, 2H), 3.90 (s, 2H), 3.61-3.86 (m, 4H), 3.51-3.58 (m,1H), 3.24 (t, J=8.8 Hz, 2H), 2.72 (t, J=6.5 Hz, 2H), 1.90-2.01 (m, 2H).MS (ES) m/z: 463.0 [M−H]

Synthesis Example 21: Compound #126(2S,3R,4R,5S,6R)-2-(5-(chroman-6-ylmethyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of 5-bromo-2,3-dihydrobenzofuran-4-ol (3.5 g, 16.28 mmol,1.00 equiv) in N,N-dimethylformamide (30 mL) with potassium carbonate(6.74 g, 48.77 mmol, 3.00 equiv) was added CH₃1 (11.56 g, 81.44 mmol,5.00 equiv). The reaction was stirred for 1 h at room temperature.NH₄Cl/H₂O was added and the mixture was extracted with EtOAc thrice. Thecombined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (3:1 PE/EA) to yield 5-bromo-4-methoxy-2,3-dihydrobenzofuran as ayellow liquid.

To a mixture of 5-bromo-4-methoxy-2,3-dihydrobenzofuran (3.3 g, 14.41mmol, 1.00 equiv) in tetrahydrofuran (50 mL) was added n-BuLi (5.76 mL,1.00 equiv, 2.5N) at −78° C. The mixture was stirred for 30 min at −78°C. After that was added N,N-dimethylformamide (2.13 g, 29.14 mmol, 2.02equiv) at −78° C. The reaction was stirred at −78° C. for 1 h. NH₄Cl/H₂Owas added and the mixture was extracted with EtOAc thrice. The combinedextracts were washed with brine and dried over Na₂SO₄. The mixture wasthen concentrated and purified by chromatography on silica gel (3:1PE/EA) to yield 4-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde as awhite solid.

To a mixture of 4-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde (2.2 g,12.35 mmol, 1.00 equiv) in methanol (30 mL) was added Pyridine.Br₃ (4.16g, 12.35 mmol, 1.00 equiv) at 0° C. The reaction was stirred for 2 h at0° C. The reaction was then quenched by the addition of 30 mL of water.The solids were collected by filtration to yield7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde as a white solid.¹H-NMR: (300 MHz, CDCl₃) δ 10.16 (s, 1H), 7.86 (s, 1H), 4.79 (t, J=9.0Hz, 2H), 4.00 (s, 3H), 3.51 (t, J=9.0 Hz, 2H).

To a mixture of 6-bromochroman (500 mg, 2.35 mmol, 1.30 equiv) intetrahydrofuran (10 mL) was added n-BuLi (0.94 mL, 1.30 equiv, 2.5N) at−78° C. The mixture was stirred for 30 min at −78° C. After that wasadded a solution of7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde (465 mg, 1.81mmol, 1.00 equiv) in tetrahydrofuran (5 mL) at −78° C. The reaction wasstirred at −78° C. for 1 h. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (3:1 PE/EA) to yield(7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)(chroman-6-yl)methanol asa yellow oil. MS (ES) m/z: 373[M-OH]⁺

To a mixture of(7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)(chroman-6-yl)methanol(600 mg, 1.53 mmol, 1.00 equiv) in dichloromethane (20 mL) with Et₃SiH(356 mg, 3.06 mmol, 2.00 equiv) was added CF₃COOH (263 mg, 2.31 mmol,1.50 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)chromane as ayellow oil. ¹H-NMR: (300 MHz, CDCl₃) δ 10.16 (s, 1H) 6.87-6.90 (m, 1H),6.82 (s, 1H), 6.69 (d, J=8.4 Hz, 1H), 3.51 (t, J=8.4 Hz, 2H), 4.11-4.16(m, 2H), 3.74-3.79 (m, 5H), 3.39 (t, J=8.4 Hz, 2H), 2.74 (t, J=8.8 Hz,2H), 1.96-2.04 (m, 2H).

To a mixture of6-((7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)chromane (137mg, 0.37 mmol, 1.10 equiv) in tetrahydrofuran (2 mL) was added n-BuLi(0.15 mL, 1.10 equiv, 2.5N) at −78° C. The mixture was stirred for 30min at −78° C. After that was added a solution of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(150 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran (2 mL) −78° C. Thereaction was stirred at −78° C. for 1 h. NH₄Cl/H₂O was added and themixture was extracted with EtOAc thrice. The combined extracts werewashed with brine and dried over Na₂SO₄. The mixture was thenconcentrated and purified by chromatography on silica gel (1:1 PE/EA) toyield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(5-(chroman-6-ylmethyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil. MS (ES) m/z: 747[M+H]⁺

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(5-(chroman-6-ylmethyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluorotetrahydro-2H-pyran-2-ol(160 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL) with Et₃SiH(50 mg, 0.43 mmol, 2.01 equiv) was added BF₃.Et₂O (46 mg, 0.32 mmol,1.51 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((7-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)chromaneas a yellow oil. MS (ES) m/z: 731 [M+H]⁺

To a mixture of6-((7-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)chromane(100 mg, 0.14 mmol, 1.00 equiv) in EA/MeOH (3:1) (10 mL) was addedPd(OH)₂/C (100 mg, 1.00 equiv) and hydrogen chloride (0.01 mL). H₂ wasintroduced. The reaction was stirred for 1 h at room temperature. Thesolids were filtered out. The mixture was then concentrated and purifiedby chromatography on a C18 reversed phase column (0%-45% CH₃CN/H₂O) toyield(2S,3R,4R,5S,6R)-2-(5-(chroman-6-ylmethyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD₃OD) δ: 7.28 (s, 1H), 6.84-6.87 (m, 2H), 6.56 (d,J=8.1 Hz, 1H), 4.66-4.69 (m, 1H), 4.51-4.63 (m, 3H), 4.08-4.12 (m, 3H),3.89-3.92 (m, 2H), 3.71-3.80 (m, 4H), 3.68 (s, 3H), 3.53-3.57 (m, 1H),3.27-3.30 (m, 1H), 2.68-2.73 (m, 2H), 1.90-1.98 (m, 2H). MS (ES) m/z:459[M−H]⁻

Synthesis Example 22: Compound #128(2S,3R,4R,5S,6R)-2-(5-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4-diol

To a mixture of 6-bromo-2,3-dihydro-1,4-benzoxathiine (585 mg, 2.53mmol, 1.30 equiv) in tetrahydrofuran (10 mL) was added n-BuLi (1.0 mL,1.30 equiv, 2.5N) at −78° C. The mixture was stirred for 30 min at −78°C. After that was added a solution of7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-carbaldehyde (500 mg, 1.94mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at −78° C. The reaction wasstirred at −78° C. for 1 h. NH₄Cl/H₂O was added and the mixture wasextracted with EtOAc thrice. The combined extracts were washed withbrine and dried over Na₂SO₄. The mixture was then concentrated andpurified by chromatography on silica gel (2:1 PE/EA) to yield(7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methanolas a yellow oil. MS (ES) m/z: 391 [M-OH]⁺

To a mixture of(7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)(2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methanol(600 mg, 1.47 mmol, 1.00 equiv) in dichloromethane (20 ml) with Et₃SiH(340 mg, 2.92 mmol, 1.99 equiv). was added CF₃COOH (250 mg, 2.19 mmol,1.50 equiv) at 0° C. The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiineas a yellow oil. ¹H-NMR: (300 MHz, CD₃OD) δ: 7.01 (s, 1H), 6.71-6.84 (m,3H), 4.65 (t, J=8.7 Hz, 2H), 4.36-4.39 (m, 2H), 3.75 (s, 5H), 3.40 (t,J=8.7 Hz, 2H), 3.10-3.14 (m, 2H).

To a mixture of6-((7-bromo-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiine(80 mg, 0.20 mmol, 1.09 equiv) in tetrahydrofuran (2 ml) was addedn-BuLi (0.08 mL, 1.10 equiv, 2.5N) at −78° C. The mixture was stirredfor 30 min at −78° C. After that was added a solution of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorooxan-2-one(84 mg, 0.19 mmol, 1.00 equiv) in tetrahydrofuran (1 ml) at −78° C.NH₄Cl/H₂O was added and the mixture was extracted with EtOAc thrice. Thecombined extracts were washed with brine and dried over Na₂SO₄. Themixture was then concentrated and purified by chromatography on silicagel (2:1 PE/EA) to yield(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(5-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluorotetrahydro-2H-pyran-2-olas a yellow oil. MS (ES) m/z: 765[M+H⁺

To a mixture of(3R,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(5-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluorotetrahydro-2H-pyran-2-ol(100 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL) with Et₃SiH(30 mg, 0.26 mmol, 1.97 equiv) was added BF₃.Et₂O (28 mg, 0.20 mmol,1.51 equiv). The reaction was stirred for 1 h at 0° C. Sodiumbicarbonate/H₂O was added and the mixture was extracted withdichloromethane thrice. The combined extracts were washed with brine anddried over Na₂SO₄. The mixture was then concentrated and purified bychromatography on silica gel (5:1 PE/EA) to yield6-((7-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiineas a yellow oil. MS (ES) m/z: 749[M+H]⁺

To a mixture of6-((7-((2S,3S,4R,5R,6R)-3,4-bis(benzyloxy)-6-((benzyloxy)methyl)-5-fluorotetrahydro-2H-pyran-2-yl)-4-methoxy-2,3-dihydrobenzofuran-5-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxathiine(60 mg, 0.08 mmol, 1.00 equiv) in dichloromethane (10 mL) with1,2,3,4,5-pentamethylbenzene (60 mg, 0.40 mmol, 5.05 equiv) was addedBCl₃ (0.6 mg, 7.50 equiv, 1 N) at −78° C. The reaction was stirred at−78° C. for 1 h. Methanol (2 mL) was added. The mixture was thenconcentrated and purified by chromatography on Prep-HPLC (0%-45%CH₃CN/H₂O) to yield(2S,3R,4R,5S,6R)-2-(5-((2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)methyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (300 MHz, CD₃OD): δ: 6.99 (s, 1H), 6.77-6.79 (m, 2H), 6.32-6.66(m, 1H), 4.51-4.59 (m, 2H), 4.32-4.38 (m, 4H), 3.65-3.83 (m, 9H),3.53-3.57 (m, 1H), 3.30-3.31 (m, 1H), 3.26-3.30 (m, 1H), 3.12-3.18 (m,2H). MS (ES) m/z: 477.0 [M−H]⁻

Synthesis Example 23: Compound #161(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl-)methyl-d2)-4-(methoxy-d3)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol

Dess-Martin reagent (943.4 mg, 2.22 mmol) was added to a solution of(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol(803 mg, 1.71 mmol) in DCM (20 ml) and the mixture was kept stirring atroom temperature for 72 h. The resulting mixture was concentrated andthe residue was purified by flash column chromatography on silica gel(40 g, EtOAc/heptane: 0>>>10%) to yield(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanoneas an orange syrup.

To a solution of(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone(500 mg, 1.07 mol) in MeOH (5 ml) was added sodium borodeuteride (179.1mg, 4.28 mmol) in three portions and the mixture was kept stirring atroom temperature for 2 h. The resulting mixture was concentrated anddiluted with 1N HCl, extracted with EtOAc three times (10 ml each time)and the combined organic extracts were dried over Na₂SO₄, filtered andconcentrated. The residue,(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methan-d-ol,was used in the next step without further purification.

To(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methan-d-olin anhydrous CH₂CO₂ at 0° C. was added Et₃SiD, followed by BF₃.Et₂O andstirred at 0° C. for 1 h, the mixture was quenched with aqueous NaHCO₃,extracted with DCM three times, concentrated and filtered. The filtratewas concentrated and the residue was purified by flash columnchromatography on silica gel (12 g, EtOAc/heptane: 0>>>10%) to yield6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl-d2)-2,3-dihydrobenzo[b][1,4]dioxineas a colorless syrup.

A 50 round-bottom flask was charged with6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl-d2)-2,3-dihydrobenzo[b][1,4]dioxine(254.7 mg, 0.56 mmol) and a magnetic stir bar and the flask wasevacuated, re-filled with nitrogen and this process was repeated twice.To the flask was added 4 ml of THF, cooled to −78° C., then n-BuLi (0.35mL, 1.6 M in hexanes) was added and the mixture was stirred at −78° C.for 35 min.(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-onein 4 ml of THF was added and the resulting mixture was stirred at −78°C. for 40 min, the reaction mixture quenched with aqueous NH₄Cl,extracted with EtOAc three times. The combined organic layer was washedwith brine, dried over N₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. The residue was dried in vacuo and re-dissolvedin ACN (10 mL) and DCM (10 mL), then cooled to −40° C. To the resultingmixture was then added triethylsilane (0.30 mL), followed by addition ofBF₃.Et₂O (0.16 mL). The reaction was kept stirring at −40° C. for 35min, then warmed to 0° C. and kept stirring at 0° C. for 1 h. Theresulting mixture was quenched with aqueous NaHCO₃, extracted with EtOActhree times. The combined organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was analyzed by LC/MS and thenre-dissolved in MeOH (4 ml). The solution was subjected to Gilson HPLCpurification (three injections) to yield(2S,3R,4R,5S,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid. ¹H NMR (METHANOL-d₄) δ: 7.43-7.52 (m, 2H), 7.29-7.39(m, 3H), 6.99-7.06 (m, 1H), 6.64-6.70 (m, 3H), 4.96-5.11 (m, 2H),4.46-4.59 (m, 3H), 4.19-4.39 (m, 1H), 4.16 (s, 4H), 3.56-3.78 (m, 4H),3.40-3.49 (m, 1H), 3.17-3.23 (m, 2H).

To a solution of(2S,3R,4R,5S,6R)-2-(4-(benzyloxy)-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(150 mg, 0.28 mmol) in EtOAc/MeOH (11 ml, 10:1 v/v) was added Pd(OH)₂(30 mg, 20%) and the flask was degassed, filled with hydrogen and this.This process was repeated three times. The mixture was kept stirring atroom temperature for 16 h. The catalyst was filtered off and thefiltrate was concentrated to yield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

To a solution of(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-4-hydroxy-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(30 mg, 0.067 mmol) in acetone (3 mL) was added K₂CO₃ (92.5 mg, 0.67mmol), followed by the addition of CD₃1. The resulting mixture was keptstirring at room temperature for 16 h. The solid was filtered and thefiltrate was concentrated. The residue was purified by Gilson HPLC toyield(2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-4-(methoxy-d3)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid (18.3 mg, 58.8%).

¹H NMR (MeOH) δ: 6.99 (s, 1H), 6.61-6.68 (m, 3H), 4.47-4.62 (m, 3H),4.19-4.41 (m, 1H), 4.16 (s, 4H), 3.52-3.81 (m, 6H), 3.25-3.29 (m, 1H).LC/MS: m/z (2M+Na): 957.2.

Example 24: Compound #101(2S,3R,4R,5S,6R)-2-[5-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-methoxy-2,3-dihydrobenzofuran-7-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol

A 2-dram vial was charged with(2S,3R,4R,5S,6R)-2-(5-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-4-hydroxy-2,3-dihydrobenzofuran-7-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol(15 mg, 0.033 mmol) and K₂CO₃ (23 mg, 0.17 mmol). To the mixture wasthen added acetone (1 ml), followed by addition of CH₃1 (8 μL), and thereaction mixture was kept stirred at room temperature for 16 h. Theresulting mixture was filtered and the filtrate was evaporated todryness under vacuum. The residue was re-dissolved in methanol (2 ml)and the solution was subjected to Gilson HPLC purification (35 ml/minflow rate, 15 min gradient time, 10%>>>90% ACN) to yield the titlecompound as a white solid.

¹H NMR (MeOH) δ: 6.97 (s, 1H), 6.66 (d, J=8.59 Hz, 1H), 6.62 (d, J=7.58Hz, 1H), 6.61 (s, 1H), 4.54 (m, 2H), 4.33 (d, J=9.09 Hz, 1H), 4.30 (m,1H), 4.16 (s, 4H), 3.79 (m, 1H), 3.73 (s, 2H), 3.71 (s, 3H), 3.63-3.70(3H), 3.53 (m, 1H), 3.31 (m, 2H). LC/MS: m/z (M+NH₄)⁺: 480.3.

Example 25: Compound #163(2S,3R,4R,5S,6R)-2-[7-[dideuterio(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-4-methoxy-2,3-dihydrobenzofuran-5-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol

To a solution of(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanone(971 mg, 2.08 mmol) in THF (30 mL) was added NaBD₄ (434.9 mg, 10.4mmol), followed by the addition of AlCl₃ (831.2 mg, 6.23 mmol). Theresulting mixture was then heated at reflux for 16 h. The mixture wasquenched with cooled NH₄Cl aqueous solution, extracted with EtOAc threetimes. The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashcolumn chromatography on silica gel (12 g, EtOAc/heptane: 0>>>15%) toyield5-bromo-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-2,3-dihydrobenzofuran-4-olas a colorless syrup.

To a solution of5-bromo-7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl-d2)-2,3-dihydrobenzofuran-4-ol(467.8 mg, 1.28 mmol) in acetone (6 ml) was added Cs₂CO₃ (626 mg, 1.92mmol), followed by the addition of CH₃1 and the mixture was maintainedwith stirring at room temperature for 4 h. The resulting solid(precipitate) was filtered off and the filtrate was concentrated. Theresidue was purified by flash column chromatography on silica gel (12 g,EtOAc/heptane: 0>>>10%>>>20%) to yield6-((5-bromo-4-methoxy-2,3-dihydrobenzofuran-7-yl)methyl-d2)-2,3-dihydrobenzo[b][1,4]dioxineas a colorless syrup.

A solution of6-((5-bromo-4-methoxy-2,3-dihydrobenzofuran-7-yl)methyl-d2)-2,3-dihydrobenzo[b][1,4]dioxine(235.5 mg, 0.62 mmol) in anhydrous THF (4 mL) was cooled to −78° C. Thevessel was evacuated and re-filled with argon, and this process wasrepeated twice. To the reaction mixture was added n-BuLi (1.6 M inhexane, 0.39 ml) dropwise and the resulting mixture was stirred at −78°C. under argon for 30 min. A solution of(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one(324.7 mg, 0.62 mmol) in THF (4 mL) was then added dropwise and theresulting reaction mixture was maintained stirring at −78° C. underargon for 1 h. The resulting mixture was then quenched with saturatedaqueous NH₄Cl solution (10 mL), extracted with EtOAc three times (10 mLeach time) and the combined extracts were washed with brine and driedwith Na₂SO₄. The resulting insoluble solid (precipitate) was filteredoff and the filtrate was concentrated under reduced pressure to yield aresidue. The residue was dissolved in acetonitrile (10 mL) and DCM (10mL) and cooled to −40° C. Triethylsilane (0.17 mL) was added, followedby addition of BF₃.Et₂O (0.090 mL). The reaction was maintained stirringat −40° C. for 35 min, then warmed to 0° C. and stirred at 0° C. for 1h. The resulting mixture was quenched with aqueous NaHCO₃ and extractedwith EtOAc three times. The combined organic layer was dried overNa₂SO₄, filtered and concentrated. The resulting residue was purified byGilson HPLC to yield the title compound as a white solid.

¹H NMR (MeOH) δ: 6.99 (s, 1H), 6.65 (s, 3H), 4.47-4.61 (m, 3H), 4.30(dt, J=51.0, 9.1 Hz, 1H), 4.16 (s, 4H), 3.82 (s, 3H), 3.50-3.78 (m, 6H),3.26 (m, 1H). LC/MS: m/z (M+NH₄)⁺: 482.1.

Example 26: Compound #172(2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-[4-methoxy-7-[(2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)methyl]-2,3-dihydrobenzofuran-5-yl]tetrahydropyran-3,4-diol

A 50 ml round-bottom flask was charged with6-bromo-2,2,3,3-tetradeuteriobenzo[b][1,4]dioxine (311 mg, 1.42 mmol)and a magnetic stir bar. The flask was evacuated, re-filled withnitrogen and this process was repeated twice. To the flask was added THF(4 mL) and the reaction mixture was cooled to −78° C. n-BuLi (1.6 M inhexanes, 0.89 mL) was added and the mixture was stirred at −78° C. for35 min. To the mixture was then added5-bromo-4-methoxy-2,3-dihydrobenzofuran-7-carbaldehyde (365 mg, 1.42mmol) in THF (16 mL) and the resulting mixture was stirred at −78° C.for 60 min. The resulting mixture was quenched with aqueous NH₄Cl, andextracted with EtOAc three times. The combined organic layer was washedwith brine, dried over N₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel (EtOAc/heptane: 0>>>10%>>>30%) toyield a white foam.

To(4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)(2,2,3,3-tetradeuteriobenzo[b][1,4]dioxin-6-yl)methan-d-olin anhydrous CH₂Cl₂ at 0° C. was added Et₃SiH (0.09 ml, 0.54 mmol),followed by BF₃.Et₂O (0.062 ml, 0.49 mmol) and the resulting mixture wasstirred at 0° C. for 1 h. The resulting mixture was then quenched withaqueous NaHCO₃, extracted with DCM three times, concentrated andfiltered. The filtrate was concentrated and the residue was purified byflash column chromatography on silica gel (12 g, EtOAc/heptane: 0>>>10%)to yield6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,2,3,3-tetradeuteriobenzo[b][1,4]dioxineas a colorless syrup.

A 50 round-bottom flask was charged with6-((4-(benzyloxy)-5-bromo-2,3-dihydrobenzofuran-7-yl)methyl)-2,2,3,3-tetradeuteriobenzo[b][1,4]dioxine(114.5 mg, 0.3 mmol) and a magnetic stir bar. The flask was evacuated,re-filled with nitrogen and this process was repeated twice. To theflask was then added THF (4 mL), and the reaction mixture was cooled to−78° C. To the reaction mixture was then added n-BuLi (0.19 mL, 1.6 M inhexanes) and the mixture was stirred at −78° C. for 35 min.(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one(157 mg, 0.3 mmol) in THF (4 mL) was added and the resulting mixture wasstirred at −78° C. for 40 min. The resulting mixture was quenched withaqueous NH₄Cl, extracted with EtOAc three times. The combined organiclayer was washed with brine, dried over N₂SO₄, filtered and the filtratewas concentrated under reduced pressure. The residue was dried in vacuoand re-dissolved in ACN (10 mL) and DCM (10 mL), then cooled to −40° C.To the resulting mixture was then added triethylsilane (0.27 mL, 1.7mmol), followed by addition of BF₃.Et₂O (0.15 mL, 1.2 mmol). Thereaction was maintained stirring at −40° C. for 35 min, then warmed to0° C. and maintained with stirring at 0° C. for 1 h. The resultingmixture was quenched with aqueous NaHCO₃, extracted with EtOAc threetimes. The combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was analyzed by LC/MS and then re-dissolved inMeOH (4 ml). The solution was subjected to Gilson HPLC purification(three injections) to yield(2S,3R,4R,5S,6R)-2-(4-(benzyloxy)-7-((2,2,3,3-tetradeuterio-1,4-benzodioxin-6-yl)methyl-d2)-2,3-dihydrobenzofuran-5-yl)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolas a white solid.

¹H NMR (MeOH) δ: 6.98 (s, 1H), 6.65 (s, 3H), 4.48-4.59 (m, 3H), 4.30(dt, J=51.3, 9.0 Hz, 1H), 3.81 (s, 3H), 3.71-3.80 (m, 2H), 3.69 (s, 2H),3.62-3.68 (m, 1H), 3.51-3.62 (m, 2H), 3.25-3.28 (m, 1H). LC/MS: m/z(M+NH₄): 484.0.

Additional representative compounds of formula (I) were preparedaccording to the procedures as described in the Examples above, withmeasured MS and ¹H NMR as listed in Table 4 below.

TABLE 4 Additional, Prepared, Representative Compounds of Formula (I) IDNo. Name, Measured ¹H NMR and MS 98(2S,3R,4R,5S,6R)-2-[5-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-hydroxy-2,3-dihydrobenzofuran-7-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol ¹H NMR (MeOH) δ: 6.86 (s, 1H),6.65 (s, 3H), 4.47-4.60 (m, 2H), 4.19-4.39 (m, 2H), 4.16 (s, 4H),3.62-3.83 (m, 6H), 3.47-3.55 (m, 1H), 3.11 (t, J = 8.6 Hz, 2H). LC/MS:m/z (M + Na)⁺: 471.1. 102(2S,3R,4R,5S,6R)-2-[5-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-ethoxy-2,3-dihydrobenzofuran-7-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol ¹H NMR (MeOH) δ: 6.98 (s, 1H),6.66 (d, J = 9.09 Hz, 1H), 6.62 (d, J = 8.59 Hz, 1H), 6.61 (s, 1H), 4.53(m, 2H), 4.33 (d, J = 9.09 Hz, 1H), 4.30 (m, 1H), 4.16 (s, 4H),3.87-3.96 (m, 2H), 3.77-3.82 (m, 1H), 3.75 (s, 2H), 3.64-3.72(3 H), 3.53(m, 1H), 3.26 (t, J = 8.59 Hz, 2H), 1.24 (t, J = 7.07 Hz, 3H). LC/MS:m/z (M + NH₄)⁺: 494.2. 160(2S,3R,4R,5S,6R)-2-[7-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-4-(trideuteriomethoxy)-2,3-dihydrobenzofuran-5-yl]-5-fluoro-6-(hydroxymethyl)tetrahydropyran-3,4-diol ¹H NMR (MeOH) δ: 6.98 (s, 1H),6.62-6.68 (m, 3H), 4.47-4.61 (m, 3H), 4.30 (dt, J = 51.0, 9.1 Hz, 1H),4.13-4.20 (m, 4H), 3.52-3.82 (m, 8H), 3.28 (m, 1H). LC/MS: m/z (M +NH₄)⁺: 483.1.

Biological Example 1: SGLT1 and SGLT2 Assay

The ability of the compounds of formula (I) of the present invention totreat an SGLT-mediated condition was determined using the followingprocedures:

SGLT1 and SGLT2 were cloned in form of cDNA from human small intestine(Genbank M24847), and from human kidney (Genbank M95549), respectively.Subsequently, each full cDNA was subcloned into pcDNA with eachconstruct's integrity verified through follow-on sequencing. To generateCHO-K1 cells that stably express human SGLT1 or human SGLT2, CHO-K1cells were transfected using DMRIE-C reagent (Life Technologies,Gaithersburg, Md.). Transfected cells were then selected in the presenceof 500 pg/ml of the Geneticin (G418 Cellgro Catalog No. 30234-Cl)

Individual clones were then characterized using the following cell-basedassay for sodium-dependent glucose transport:

Inhibition of SGLT1 and SGLT2 activity was assessed in CHO K1 cellsstably expressing either human SGLT1 or SGLT2, using the SGLT specificglucose analog methyl-glucopyranoside (Sigma Catalog No. M-9376). Cellswere plated (45,000 cells/well) in white wall 96-well plates (COSTAR,Cat#3903) for 24 hours in growth medium, then a final concentration of10 mM Na-Butyrate (ALDRICH Cat#30341-0) was added. The cells wereincubated for 24 hours. On the day of the assay, cells were rinsed andtreated with test compounds (at concentrations of 0.001 pM to 10 pM) inassay buffer (50 mM HEPES, 20 mM Tris base, 5 mM KCl, 1 mM MgCl₂, 1 mMCaCl₂ and 137 mM NaCl, pH 7.4) for 10 minutes. Cells were then incubatedwith ¹⁴C-a-methyl-d-glucopyranoside (AMG, Amersham Catalog No. CFB 76),using 0.07 μCi per well in 500 μM AMG final concentration. The cellswere incubated for 2 hours at 37° C. with 5% CO₂ and washed two timeswith ice-cold Phosphate Buffer Solution (Cellgro Catalog No. 21030-CV).The cells were then solubilized by adding 60 μl of MICROSCINT™20 and theNa-dependent ¹⁴C-AMG uptake was quantified by measuring radioactivity.Plates were counted in a TopCount (Packard, Meriden, Conn.)

Representative compounds of the present invention were tested accordingto the procedures as described in Biological Example 1 and 2 above, withresults as listed in Table 5, below. Results are reported as the%-inhibition or IC₅₀ value. Variability for the functional assay wastypically within 20%. The %-inhibition or IC₅₀ data were derived fromthe best curve fit as listed in Table 5, below. When a listed compoundwas tested more than once, the average is listed in Table 5 below.

TABLE 5 SGLT1 and SGLT2 Activity SGLT1 SGLT2 ID No. IC₅₀ (μM) IC₅₀ (μM)2 0.009 0.008 4 0.014 0.004 7 0.018 0.006 9 0.126 0.107 10 0.085 0.08211 0.091 0.059 12 0.100 0.024 13 0.015 0.007 14 69.3% @ 0.3 μM 36.0% @0.3 μM 15 0.100 0.068 16 0.111 0.029 18 0.068 0.018 19 47.6% @ 0.3 μM68.1% @ 0.3 μM 20 0.114 0.402 21 0.313 0.112 22 62.7% @ 0.3 μM 0.241 2365.2% @ 0.3 μM 0.069 24 0.977 0.332 26 0.847 0.982 28 50.3% @ 0.3 μM 290.013 0.062 30 51.0% @ 0.3 μM 31 0.009 0.019 32 15.3% @ 0.3 μM 34 38.6%@ 0.3 μM 27.6% @ 0.3 μM 39 0.381 0.123 42 0.098 0.010 52 0.015 0.009 530.104 0.026 54 0.069 0.011 56 0.523 0.012 59 0.031 0.009 61 0.014 0.00362 0.048 0.004 63 0.122 0.004 64 0.156 0.036 65 0.043 0.009 66 0.0400.014 67 64.9% @ 0.3 μM 57.5% @ 0.3 μM 68 0.055 0.021 69 20.4% @ 0.3 μM60.3% @ 0.3 μM 70 0.100 0.162 71 76.4% @ 0.3 μM 30.0% @ 0.3 μM 72 0.1270.024 73 0.240 0.048 74 65.5% @ 0.3 μM 65.2% @ 0.3 μM 75 61.9% @ 0.3 μM43.7% @ 0.3 μM 76 28.6% @ 0.3 μM 72.2% @ 0.3 μM 77 30.3% @ 0.3 μM 69.9%@ 0.3 μM 78 28.4% @ 0.3 μM 86.9% @ 0.3 μM 79 0.126 0.137 80 37.4% @ 0.3μM 60.4% @ 0.3 μM 81 0.223 0.011 82 42.2% @ 0.3 μM 58.9% @ 0.3 μM 8317.4% @ 0.3 μM 72.3% @ 0.3 μM 84 0.101 0.036 85 37.4% @ 0.3 μM 10.1% @0.3 μM 86 0.290 0.038 87 48.7% @ 0.3 μM 59.0% @ 0.3 μM 88 42.5% @ 0.3 μM44.8% @ 0.3 μM 89 0.042 0.100 90 30.9% @ 0.3 μM 54.9% @ 0.3 μM 91 31.7%@ 0.3 μM 65.5% @ 0.3 μM 92 29.0% @ 0.3 μM 76.2% @ 0.3 μM 93 33.6% @ 0.3μM 42.3% @ 0.3 μM 94 32.6% @ 0.3 μM 19.2% @ 0.3 μM 95 45.3% @ 0.3 μM62.7% @ 0.3 μM 96 29.1% @ 0.3 μM 18.2% @ 0.3 μM 97 31.2% @ 0.3 μM 67.9%@ 0.3 μM 98 30.9% @ 0.3 μM 26.0% @ 0.3 μM 99 28.9% @ 0.3 μM 83.5% @ 0.3μM 100 0.095 0.008 101 0.096 0.007 102 27.6% @ 0.3 μM 40.7% @ 0.3 μM 1030.086 0.003 104 32.5% @ 0.3 μM 81.2% @ 0.3 μM 105 0.128 0.004 106 29.4%@ 0.3 μM 82.1% @ 0.3 μM 107 0.163 0.008 108 0.326 0.075 109 39.5% @ 0.3μM 72.7 @ 0.3 μM 110 1.421 0.005 111 0.101 0.019 112 0.376 0.023 11321.0% @ 0.3 μM 53.9% @ 0.3 μM 114 0.109 0.005 115 35.6% @ 0.3 μM 79.3% @0.3 μM 116 11.5% @ 0.3 μM 78.0% @ 0.3 μM 117 44.3% @ 0.3 μM 69.9% @ 0.3μM 118 0.050 0.002 119 0.156 0.011 120  6.6% @ 0.3 μM 54.7% @ 0.3 μM 12120.5% @ 0.3 μM 79.8% @ 0.3 μM 122 31.7% @ 0.3 μM 63.6% @ 0.3 μM 1231.356 0.100 124 0.698 0.147 125 0.227 0.017 126 21.7% @ 0.3 μM 16.8% @0.3 μM 127 63.2% @ 0.3 μM 78.4% @ 0.3 μM 128 0.187 0.062 129 0.176 0.007130 44.8% @ 0.3 μM 81.6% @ 0.3 μM 131 0.231 0.012 132 0.135 0.023 1330.236 0.006 134 0.254 0.012 135 0.085 0.008 138 37.5% @ 0.3 μM 46.7% @0.3 μM 142 59.8% @ 0.3 μM 85.8% @ 0.3 μM 152 0.006 0.006 153 0.050 0.058154 0.042 0.002 156 0.086 0.010 157 47.7% @ 0.3 μM 61.9% @ 0.3 μM 158 2.6% @ 0.3 μM 18.0% @ 0.3 μM 159  6.0% @ 0.3 μM  0.0% @ 0.3 μM 1600.071 0.008 161 0.052 0.007 163 0.050 0.008 165 0.056 0.016 166 0.2450.011 167 37.9% @ 0.3 μM 80.1% @ 0.3 μM 169 37.2% @ 0.3 μM 72.7% @ 0.3μM 171 27.1% @ 0.3 μM 69.9% @ 0.3 μM 172 0.045 0.007 173 0.190 0.013 1750.087 0.012 176 68.9% @ 0.3 μM 56.1% @ 0.3 μM 178 42.0% @ 0.3 μM 70.7% @0.3 μM 179 0.060 0.015 180 0.061 0.025 181 67.0% @ 0.3 μM 85.0% @ 0.3 μM182 0.138 0.011

Formulation Example 1 Solid, Oral Dosage Form—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of the Compound#61, prepared as in Example 14 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

1-19. (canceled)
 20. A compound of formula (V-S)

wherein A¹, A² and A³ are each an independently selected from the groupconsisting of C₁₋₈alkyl, C₃₋₆cycloalkyl, bicyclo[2.2.1]heptan-2-yl,phenyl and 3,5-di(trifluoromethyl)phenyl.
 21. A compound as in claim 20,wherein A¹ is methyl, A² is methyl and A³ is t-butyl; or A¹ is methyl,A² is methyl and A³ is 2,3,3-trimethylbutan-2-yl; or A¹ is methyl, A² ismethyl and A³ is isopropyl; or A¹ is methyl, A² is methyl and A³ iscyclohexyl; or A¹ is methyl, A² is methyl and A³ isbicyclo[2.2.1]heptan-2-yl; or A¹ is methyl, A² is methyl and A³ isphenyl; or A¹ is methyl, A² is methyl and A³ is3,5-di(trifluoromethyl)phenyl; or A¹ is t-butyl, A² is phenyl and A³ isphenyl.
 22. A compound as in claim 20, wherein the compound of formula(V-S) is(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one.23. A process for the preparation of a compound of formula (V-S)

wherein A¹, A² and A³ are each an independently selected from the groupconsisting of C₁₋₈alkyl, C₃₋₆cycloalkyl, bicyclo[2.2.1]heptan-2-yl,phenyl and 3,5-di(trifluoromethyl)phenyl; comprising

reacting(2S,3R,4S,5R,6R)-2-(allyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,with an acylating agent; in the presence of an inorganic or organicbase; neat, when in the presence of an organic base or when in thepresence of an inorganic base, in an organic solvent; at a temperaturein the range of from about −50° C. to about room temperature; to yieldthe corresponding compound of formula (A-1), wherein W is thecorresponding acyl group, preferably —C(O)-methyl, —C(O)-ethyl,—C(O)-benzyl, more preferably —C(O)-benzyl (benzoyl);

reacting the compound of formula (A-1) with a fluorinating agent; in anorganic solvent or mixture of organic solvents; at a temperature in therange of from about −50° C. to about room temperature; to yield thecorresponding compound of formula (A-2);

de-protecting the compound of formula (A-2) to yield(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol;

reacting(2S,3R,4R,5S,6R)-2-(allyloxy)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diolwith a trialkyl silyl reagent; in the presence of an organic base; in anorganic solvent or mixture of organic solvents; at a temperature in therange of from about 0° C. to about 50° C.; to yield the correspondingcompound of formula (A-3) wherein A¹, A² and A³ are the correspondingalkyl groups;

reacting the compound of formula (A-3) with allyl isomerization catalystin an organic solvent or mixture of water and a water miscible organicsolvent; at a temperature of in the range of from about 75° C. to about105° C.; to yield the corresponding compound of formula (A-4), whereinthe compound of formula (A-4) is not isolated;

reacting the compound of formula (A-4) with an co-oxidant; in thepresence of an oxidizing reagent; in an organic solvent or mixture ofwater and a water miscible organic solvent; at a temperature in therange of from about 0° C. to about 50° C.; to yield the correspondingcompound of formula (A-5);

reacting the compound of formula (A-5) under SWERN oxidation conditions;to yield the corresponding compound of formula (V-S).
 24. A process asin claim 23, wherein A¹ is methyl, A² is methyl and A³ is t-butyl; or A¹is methyl, A² is methyl and A³ is 2,3,3-trimethylbutan-2-yl; or A¹ ismethyl, A² is methyl and A³ is isopropyl; or A¹ is methyl, A² is methyland A³ is cyclohexyl; or A¹ is methyl, A² is methyl and A³ isbicyclo[2.2.1]heptan-2-yl; or A¹ is methyl, A² is methyl and A³ isphenyl; or A¹ is methyl, A² is methyl and A³ is3,5-di(trifluoromethyl)phenyl; or A¹ is t-butyl, A² is phenyl and A³ isphenyl.
 25. A process as in claim 23, wherein the compound of formula(V-S) is(3R,4R,5R,6R)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorotetrahydro-2H-pyran-2-one.26. A compound prepared according to the process of claim 23.